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Josephine Janz Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Nizar W. Shayya Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Stefan Bereswill Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Markus M. Heimesaat Gastrointestinal Microbiology Research Group, Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

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Open access

Abstract

The widespread misuse of antibiotics leads to a rapid development of multi-drug resistant (MDR) bacterial pathogens all over the globe, resulting in serious difficulties when treating infectious diseases. Possible solutions are not limited to the development of novel synthetic antibiotics but extend to application of plant-derived products either alone or in combination with common antibiotics. The aim of this actual review was to survey the literature from the past 10 years regarding the antibacterial effects of distinct Artemisia species including Artemisia absinthiae constituting an integral component of the Absinthe drink. We further explored the synergistic antibacterial effects of the Artemisia plant products with established antibiotics. The survey portrays the Artemisia derived compounds as potent antibacterial agents that can even restore the efficacy of antibiotics against MDR bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and MDR Escherichia coli. This, in turn, is presumably triggered in part by the interaction of the Artemisia ingredients with the efflux pumps of MDR bacteria. In conclusion, biologically active molecules in Artemisia plants enhance the antibiotic susceptibility of resistant bacteria, which provide promising future therapeutic strategies to combat MDR bacterial pathogens.

Abstract

The widespread misuse of antibiotics leads to a rapid development of multi-drug resistant (MDR) bacterial pathogens all over the globe, resulting in serious difficulties when treating infectious diseases. Possible solutions are not limited to the development of novel synthetic antibiotics but extend to application of plant-derived products either alone or in combination with common antibiotics. The aim of this actual review was to survey the literature from the past 10 years regarding the antibacterial effects of distinct Artemisia species including Artemisia absinthiae constituting an integral component of the Absinthe drink. We further explored the synergistic antibacterial effects of the Artemisia plant products with established antibiotics. The survey portrays the Artemisia derived compounds as potent antibacterial agents that can even restore the efficacy of antibiotics against MDR bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and MDR Escherichia coli. This, in turn, is presumably triggered in part by the interaction of the Artemisia ingredients with the efflux pumps of MDR bacteria. In conclusion, biologically active molecules in Artemisia plants enhance the antibiotic susceptibility of resistant bacteria, which provide promising future therapeutic strategies to combat MDR bacterial pathogens.

Introduction

The topic of antimicrobial resistance has increasingly gained the world’s attention in the past years. The World Health Organization (WHO) organizes an annual event, the World Antimicrobial Awareness Week, as part of the ‘Antimicrobials: Handle with care’ campaign, aiming to raise public interest about this serious issue. Importantly, in 2021, the topic ‘Spread awareness, stop resistance’ shed light onto the burden of multi-drug resistant (MDR) pathogens on the health care system, which, for the most part, results from the misuse of antimicrobials such as antibiotics, antivirals, antifungals and antiparasitics in human and veterinary medicine [1, 2]. Consequently, the WHO implemented a global action plan on antimicrobial resistance to address these serious health issues, particularly antibiotic resistance of distinct bacterial pathogens against several antibiotics [3].

Antimicrobial resistance has existed for a long time. In fact, the earliest evidence of resistance against ß-lactam, tetracycline and glycopeptide antibiotics can be scientifically traced back 30,000 years [4]. In 1909, the antibiotic era was heralded by the discovery of the arsenic compound Arsphenamin (Salvarsan®) by Paul Ehrlich. Then, following discovery and medical application of the sulphonamides and penicillins, resistant bacteria arose limiting treatment of infectious diseases. Nevertheless, the development of bacterial resistances constituted an ancient evolutionary phenomenon arising long before the discovery of antibiotics by mankind [5]. While primary (i.e., intrinsic) resistance is innate and based on bacterial characteristics, such as the glycopeptide resistance of Gram-negative bacteria, secondary resistance is acquired or adaptive. Additionally, acquired resistance can develop via mutations, through horizontal or vertical gene transfer, whereas adaptive resistance is a reaction triggered by environmental factors such as stress, growth conditions, pH, ion concentrations, and sub-inhibitory concentrations of antibiotics, for instance [6]. Adaptive resistance is unstable and results from epigenetic modifications of bacterial DNA. This renders bacteria versatile and highly adaptive to environmental changes [7]. Moreover, the rapid increase in drug resistance is not only due to the agricultural application of antibiotics, but also to the widespread misuse of antibiotics in human as well as veterinary medicine which leads to higher survival rates of bacteria, and the emergence of MDR pathogenic strains [8, 9]. This, in turn, leads to high mortality rates in the population due the increased complexity of treating these infections. This highlights the necessity to develop alternative or combinational therapies that target infections caused by MDR bacterial pathogens [10, 11]. One such promising approach might be the return to traditional medicine benefitting from thousands of years of empirical experience given that the antimicrobial effects of distinct natural products have been known for long.

The Artemisia genus belongs to the family of Asteraceae and includes approximately 250–500 species, most of which can be found in the Mediterranean region and Asia [12]. Plants of the Artemisia genus provide a high therapeutic potential and have been applied for various medicinal purposes since ancient times, including inflammatory conditions due to gastrointestinal and pulmonary infections [13]. For instance, Artemisia annua (also called Qinghaosu, Sweet Sagewort, Sweet Annie, Sweet Wormwood, Annual Wormwood) has been used to treat malaria for at least 1,600 years [14]. Another example, Artemisia absinthium (also known as absinthium, absinth sagewort, absinth wormwood and common sagewort) constituting the main ingredient in the popular Absinthe drink has been successfully applied in ancient Greece and in traditional medicine of Western Europe [15]. It is estimated that nowadays 70–95% of the human population worldwide relies on the health beneficial actions exerted by plant derived natural products in primary health care [16]. Particularly in Traditional Chinese Medicine natural products derived from Artemisia plants are of great medicinal impact. Furthermore, in compliance to worldwide guidelines an “Artemisinin-based combination therapy” (with artemether plus lumefantrine and artesunate plus sulfadoxine-pyrimethamine or dihydroartemisinin plus pipraquin) represents the pivotal treatment of malaria for long [17, 18]. Notably, in a murine model artemisone and artemiside was shown to control both, acute and reactivated disease following infection by the apicomplexan parasite Toxoplasma gondii [19].

Importantly, the primary ingredient of respective combinations is a compound of artemisinin, which constitutes an active agent in most of the plants of the Artemisia genus [20]. On top of that, many studies addressed the antimicrobial, anticancer, antiinflammatory, antipyretic, antiparasitic and antioxidant properties of plants from the Artemisia genus [14, 21]. These effects can be traced back to the biologically active molecules within the Artemisia plants, which have been identified in diverse compounds including flavonoids, monoterpenoids, sesquiterpenoids (e.g. artemisinin), coumarins, and aliphatic and lipid compounds [15, 22–26].

The primary goal of our literature survey was to provide an actual overview of the effects of Artemisia derived plant products and its biologically active agents on bacterial including MDR strains. We also aimed to assess the capacity of these different plant products to enhance the antibiotic susceptibility of MDR bacteria when combined with conventional antibiotics.

Methods

General inclusion and exclusion criteria

We included studies i.) addressing the antibacterial effects of different Artemisia species (see Search query); ii.) focusing on different biologically active substances derived from Artemisia plants; iii.) assessing antimicrobial effects directed against defined bacteria by applying distinct methods. Studies addressing antimalarial effects were excluded manually. Furthermore, all studies referring to antihelminthic, antifungal and anticancer effects of Artemisia species had to be excluded as well as the investigations on chemical engineering of Artemisia plants. In order to provide an actual overview of knowledge we summarized the most recent findings from the past 10 years. Therefore, studies from before 2011 were excluded.

Search query

This literature survey was performed by using the MEDLINE database PubMed from September 14th to September 22nd, 2021. Our aim was to outline the topic as precisely as possible without excluding relevant studies.

First, we searched the database for publications that include the keyword “artemisia”. Therefore, we searched all fields through the Medical Subject Headings MeSH to ensure all terms were included, and combined them with the Boolean operator “OR”. Search #1 was “artemisia”[MeSH Terms] OR “artemisia*”[All Fields]. For search #2 the target was antibacterial agents applying “anti bacterial agents”[Pharmacological Action] OR “anti bacterial agents”[MeSH Terms] OR “anti bacterial*”[All Fields] OR “antibacterial*”[All Fields] OR “anti infective agents”[Pharmacological Action] OR “anti infective agents”[MeSH Terms] OR (“anti infective*”[All Fields] OR “antimicrobial*”[All Fields]). For search #3, we used (“multidrug*”[All Fields] OR (“multi”[All Fields] AND “drug*”[All Fields])) AND “resist*”[All Fields] to target multidrug resistance. Then, for search #4, we combined this search with “Drug Resistance, Microbial”[Mesh] OR “Drug Resistance, Multiple”[Mesh] using the Boolean operator “OR”, to ensure all the publications that target drug resistance are included. Finally, to limit the spectrum of results, we combined search #1, #2 and #4, using the Boolean operator “AND”. The final search yielded 76 results. 24 studies related to malaria were excluded manually, five of which addressed phytotherapy and combination therapies which were not in the focus of our literature survey. Eleven studies investigating the physical or chemical properties of Artemisia species and the measures to increase the yield of artemisinin in a plant were excluded, which was also the case for 10 studies on the role of Artemisia plants in anticancer, antihelminthic or antifungal treatments. Furthermore, five studies addressing the biosynthesis of nanoparticles created from medicinal plants, and another two epidemiological surveys were also excluded. Another two surveys targeting the potential of toxicity and endophytes derived from the Artemisia plant were excluded as well. Out of the remaining 19 studies, we included the studies that had been conducted in the last ten years which, in turn, led to total of 14 studies, seven of which were less than three years old. The data collection was carried out in compliance with Charité’s regulations for ensuring good scientific practice [27] and adherence to legal data protection.

Results

Antibacterial effects of Artemisia absinthium

Plant extracts have been used in traditional medicine for long and are important for inhibiting bacterial growth and biofilm formation, as well as for bacterial cytotoxicity and quorum quenching [12, 28]. Khan et al. assessed the role of different medicinal plants from Pakistan including Artemisia absinthium extracts against the “ESKAPE pathogens”, namely E scherichia coli, S taphylococcus aureus, K lebsiella pneumoniae, A cetinobacter baumannii, P seudomonas aeruginosa and E nterococcus faecium, displaying pronounced resistance rates. Interestingly, ethanol extracts of A. absinthium exhibited a dose-dependent antibacterial activity exclusively against the tested Gram-positive bacteria such as S. aureus and E. faecium with an MIC50 value of 256 μg ml−1, resulting in at least 50% bacterial growth inhibition as tested by the broth microdilution method. The authors further assessed inhibition of bacterial quorum sensing and quorum quenching by using four reporter strains of S. aureus arg subtypes. Whereas a modest inhibition of quorum sensing could be measured with the ethanol as well as the aqueous extract of A. absinthium, no effect on quorum quenching could be observed. Furthermore, neither A. absinthium extract affected bacterial biofilm formation [28].

Another study conducted by Fiamegos et al., who investigated A. absinthium and its antibacterial effects on E. coli, Enterococcus faecalis and Bacillus cereus, revealed that chloroform extracts of A. absinthium alone did not exert any antimicrobial effects. However, when combined with 30 μg ml−1 of berberine, the growth of the afore-mentioned bacteria could be successfully inhibited. Among the major compounds of A. absinthium analyzed in terms of antimicrobial activity in this study, 4′,5′-O-dicaffeoylquinic acid (4′,5′-ODCQA), a dicaffeoylquinic acid isomer, was the only molecule shown to exhibit antimicrobial activity against the Gram-positive bacteria with a minimal inhibitory concentration (MIC) of 64 μg ml−1. Importantly, 4′,5′-ODCQA was identified as a specified efflux pump inhibitor for the Major Facilitator Super Family multi-drug efflux pumps of Gram-positive bacteria including S. aureus and E. faecalis [29].

Antibacterial effects of Artemisia annua

Artemisinin, a metabolite of the Artemisia annua plant, is known to possess potent antimicrobial and immunomodulatory features [30]. Four studies addressed the antibacterial effects of extracts and biologically active compounds of Artemisia annua [30]. In a study conducted by Goswami et al. [31], the authors investigated the antibiotic susceptibility of Helicobacter pylori towards artemisinin and its derivatives applying both, agar disc diffusion and broth dilution assays. The results showed that the compounds exhibited MICs of 2–8 μg ml−1 and minimal bactericidal concentrations (MBCs) of 4–8 μg ml−1 against H. pylori. Interestingly, artemether, an artemisin derivative, could completely overcome H. pylori drug resistance in this study. These compounds were also able to induce major deformations in the morphology of the H. pylori bacteria. Moreover, the antibacterial spectrum of artemisin and its derivatives was not limited to H. pylori, but was also extended to S. aureus, Staphylococcus epidermidis, Streptococcus mutans, B. subtilis, E. coli, and Enterobacter aerogenes [31].

Rolta et al. examined the synergistic effect of distinct antibiotic compounds in combination with the methanol and petroleum extracts of Artemisia annua directed against E. coli and S. aureus isolates [31]. The extracts did not only exert significant antibacterial activities by themselves, but also significant synergistic effects upon combination with defined antibiotics. For instance, for the methanol ether extract of A. annua MICs of 62.5 μg ml−1 against E. coli and S. aureus could be assessed, while the MICs of the petroleum ether extract against respective strains were 125 μg ml−1. Against E. coli the MIC of both, chloramphenicol and kanamycin were 7.81 μg ml−1, whereas vancomycin and erythromycin exhibited MICs of 250 μg ml−1 and 500 μg ml−1, respectively. Chloramphenicol displayed a MIC of 125 μg ml−1 against S. aureus, whereas vancomycin, tetracycline and kanamycin showed a MIC of 250 μg ml−1 and erythromycin a MIC of 500 μg ml−1. Upon combination, however, the methanol ether extract decreased the MICs of vancomycin, erythromycin, chloramphenicol and kanamycin by 8-fold in E. coli which was also true for S. aureus, while the MIC of tetracycline was decreased by 8-fold against E. coli and by even 15-fold against S. aureus. On the other hand, the petroleum ether extract decreased the MICs of vancomycin, erythromycin and tetracycline by 8-fold and, interestingly, the MIC of kanamycin was decreased by 32-fold against E. coli. As for the MICs of vancomycin and erythromycin, they were decreased by 4- and 8-fold against S. aureus, respectively, whereas the MICs of chloramphenicol, tetracycline and kanamycin against S. aureus were decreased by 128-, 16- and 8-fold, respectively. This study also revealed that the main components in both extracts were phenolics, flavonoids, phytosteroids, alkaloids, glycosides, proteins and free amino acids [31].

In a very recent study, Golbarg and colleagues investigated the antibacterial properties of the essential oil, the aqueous and the ethanolic extracts of A. annua against MDR E. coli isolates by using microdilution and agar well diffusion assays [32]. The essential oil was the most potent plant product as it inhibited the bacterial growth with an inhibition zone diameter (IZD) of 20.0 ± 1.45 mm at a concentration of 11.11 mg ml−1 (11,110 μg ml−1), with a respective MIC of 10−4 mg ml−1 (0.1 μg ml−1), whereas the ethanol extract of A. annua exerted an identical MIC. When compared to distinct synthetic antibiotics, the essential oil was the most potent compound with an inhibitory effect of 56.7% when assessing all tested isolates and notably, exhibited antibacterial effects that were comparable to those observed with oxacillin, ampicillin, amoxicillin, amoxicillin-clavulanic acid, tetracycline, streptomycin, ceftriaxone, ciprofloxacin, cefuroxime, cefazolin, ceftazidime and cefixime. The authors further analyzed the phytocompounds in the extracts in more detail. The obtained results revealed the abundances of monoterpenes (alpha-pinene, camphene, 1,8-cineole, terpineol, Z-beta, cis-sabinene hydrate, borneol, Myrtenol, trans-(+)-carveol, and verbenene), sesquiterpenes (alpha-copaene, trans-caryophyllene, germacrene, beta-selinene, bicyclogermacrene, caryophyllene oxide and ledene), diterpene, cycloalkanes, cycloalkenes, alkyne and aldehyde in the essential oil. The authors suggested that the reason for the enhanced antimicrobial potency of the essential oil might be due to the abundance of various antibacterial molecules. In both plant extracts, polyphenolic compounds including catechins and chlorogenic acid could be found, whereas in the aqueous extract only chlorogenic acid was detectable. Furthermore, the aqueous extract displayed higher catechin concentrations [32].

Antimicrobial effects of Artemisia species directed against distinct bacteria

Mycobacterium species

In the past years the antimalarial compound artemisinin has gained significant attention as a promising tuberculostatic drug [33, 34]. Martin et al. examined the antimicrobial effects of Artemisia afra and A. annua against Mycobacterium tuberculosis, Mycobacterium abscessus and Mycobacterium smegmatis [33]. Therefore, A. annua and A. afra were resuspended in dichloromethane acquiring extracts with a yield of 0.82% and ≤0.0077% of the active agent artemisinin, respectively. The MICs of the plant extracts of A. annua and A. afra against the tested mycobacterial species were 39 μg ml−1 and <0.37 μg ml−1 respectively, whereas the MIC of pure artemisinin was 75 μg ml−1. These results indicate that the observed antimycobacterial activities cannot be traced back to the presence of artemisinin as an active agent only, but also to the combination of artemisinin with additional compounds, since upon increasing artemisinin concentration by 2-fold (i.e., from 150 μg ml−1 to 300 μg ml−1), the bactericidal effect did not change, meanwhile an equivalent increase in A. annua concentration significantly enhanced the bactericidal activity against M. tuberculosis. Furthermore, A. afra exhibited bactericidal activities to a lesser extent, which might be explained by the lower artemisinin concentration in the plant. The antimycobacterial effect of A. afra was, however, still more pronounced when compared to pure artemisinin. Importantly, the bactericidal properties of the plant extract were similar when compared to the effects exerted by antimycobacterial drugs, such as rifampicin, isoniazid, ethambutol, streptomycin and ofloxacin. Of note, A. annua exhibited significant bacteriostatic activities on the intrinsically more resistant M. abscessus strain, which was not the case for pure artemisinin and A. afra [33].

Furthermore, a study conducted by Gemechu et al. addressed the antibacterial activities of methanol extracts of Artemisia abyssinica leaves against different M. tuberculosis and Mycobacterium bovis strains [34]. In this study, the extract exhibited MICs ranging from 6.25 to 50.0 μg ml−1 against the M. tuberculosis and from 12.5 to 50.0 μg ml−1 against the M. bovis strains under investigation. The extract showed a prominent antimycobacterial activity, but yet was less biologically active than the common antimycobacterial drug rifampicin [34].

Escherichia coli

In section Antibacterial effects of Artemisia annua, we have already reported the antibacterial effect of some Artemisia species against E. coli. In addition, Smirnova et al. investigated the effect of the plant polyphenols quercetin, rutin, tannin, catechin, naringenin and hesperetin contained in the Artemisia species A. austriaca and A. pontica [35]. Of note, this was the only study within this survey that did not reveal antibacterial activity, but, on the contrary, showed an even enhanced bacterial growth-promoting effect. In fact, the polyphenols did not exert synergistic effects with the tested synthetic antibiotics and, interestingly, the MICs even increased from 0.03 μg ml−1 to 0.125 μg ml−1 and to 0.25 μg ml−1 for ciprofloxacin with polyphenols from A. austriaca and A. pontica, respectively. As for kanamycin, the MIC increased from 16 μg ml−1 to 64 μg ml−1 and to 128 μg ml−1, which corresponded to a 4- and 8-fold increase for A. austriaca and A. pontica, respectively. This rather “protective” effect against the antibacterial activity of ciprofloxacin may have been due to iron metabolism recovery in the presence of the plant extracts. Additionally, the authors hypothesized that the antioxidant properties of the plant extracts contributed to this enhanced antibiotic resistance through several suggested mechanisms, including radical scavenging, iron chelation and inducing genes that encode antioxidant enzymes [35].

Further, a study conducted by Chebbac et al., focused on the antibacterial activity of the essential oil of Artemisia negrei, a medicinal plant found in Morocco, against E. coli [36]. The essential oil displayed potent antibacterial effects against the two E. coli islates tested, with MIC values of 6.25 μg ml−1. Importantly, the essential oil of A. negrei contains a relatively high amount of oxygenated monoterpenes, which explains the high antioxidant and antimicrobial activity and suggests it as a potential source of radical scavenging [36].

Antimicrobial effects of further Artemisia species

As mentioned earlier, the Artemisia genus comprises a high number of species which can be found around the globe and exert significant antimicrobial, antioxidant and anti-inflammatory effects. In a study investigating the chemical composition of Artemisia phaeolepis and the antimicrobial activities of the essential oil and its major components [37], the obtained results revealed potent antimicrobial effects against S. aureus, B. subtilis, E. coli, P. aeruginosa, Listeria monocytogenes and Salmonella enterica. The agar diffusion tests showed an IZD of >21.0 mm for the essential oil itself, whereas the active agents contained in A. phaeolepis eucalyptol and germacrene D resulted in an IZD of >20.9 mm and >22.2 mm, respectively. In fact, these tested compounds proved even more effective than the synthetic antibiotics streptomycin and tetracycline which induced IZDs of >20.0 mm and >21.5 mm, respectively. Caryophyllene oxide, another phytocompound, had the least IZD with <13.7 mm. When applying the broth dilution assays, the MICs of the phytocompounds camphor and terpine-4-ol were 31.25–62.5 μg ml−1 and 62.5–125 μg ml−1, respectively, whereas the essential oil MICs ranged from 62.5 to 125.0 μg ml−1, which were comparable to the germacrene D MICs. Caryophyllene and caryophyllene oxide exhibited the least pronounced antibiotic activity with MICs >125 μg ml−1. The results suggest that the pronounced antibacterial activities of most of the compounds under investigation and the essential oil of A. phaeolepis itself were due to the antibacterial potential of the monoterpenes. In the phytochemical analysis further phytocompounds of the A. phaeolepis essential oil were identified as sabinene, ß-pinene, limonene, linalool, borneol, spatulenol and thujone. The authors hypothesized that respective phytocompounds might additionally contribute to the antimicrobial effect of the essential oil and in fact, synergistic effects may not be ruled out [37].

Another study addressed the antibacterial effects of other Artemisia species against P. aeruginosa [38]. Therefore, the antibacterial capacity of the compound dihydroleucine (DhL), a sesquiterpene lactone contained in Artemisia douglasiana, was tested against distinct P. aeruginosa isolates. In fact, DhL inhibited 50% of the bacterial growth of different P. aeruginosa strains, including the clinical MDR strain CDN118, at concentrations ranging from 120 to 480 μg ml−1. The study also revealed DhL MICs of 480 μg ml−1 and 960 μg ml−1 against P. aeruginosa reference strains, as well as a lower MIC of 280 μg ml−1 when tested against the MDR strain, indicating that DhL was bacteriostatic for virulent strains PA14 and DCN118, but bactericidal for the less virulent strains PAO1 and PA103. Furthermore, DhL did not only exhibit a significant antibacterial activity against the P. aeruginosa strains, but on note, also exerted significant synergistic effect upon combination with the synthetic antibiotics gentamicin, chloramphenicol and ciprofloxacin [38].

Another study examined the antibacterial properties of Artemisia rupestris and its components, namely the five flavonoids artemetin, chrysosplenetin, pachypodol, penduletin and chrysoeriol highlighting the importance of developing resistance-modifying agents from natural products by investigating the synergistic effect of the compounds with existing antibiotics [39]. Upon combination with norfloxacin, chrysosplenetin, penduletin and chrysoeriol inhibited the bacterial growth of a fluoroquinolone-resistant S. aureus strain, reducing the MIC of the antibiotic by 4-, 16- and 4-fold, respectively. Interestingly, the combination of chrysoeriol and ciprofloxacin strongly inhibited the bacterial growth of one methicillin-resistant S. aureus (MRSA) strain, reducing the MICs by 128-fold from 64 μg ml−1 to 0.5 μg ml−1. Furthermore, chrysoeriol reduced the MIC of oxacillin against another MRSA strain by 8-fold from 128 μg ml−1 to 16 μg ml−1. Moreover, this study suggests that the molecular mechanism responsible for this synergistic antimicrobial activity, resulting from a drug efflux inhibitory effect, was accomplished by inhibiting the mRNA expression of the efflux pump or by directly binding to the NorA receptor [39].

Additionally, Choi et al. studied the antimicrobial effects of another Artemisia species, namely Artemisia princeps, against MRSA [40]. Interestingly, the ethanol extract of A. princeps showed a dose-dependent antibacterial activity, with significant inhibition at concentrations below 1 mg ml−1 (1,000 μg ml−1). Moreover, the extract strongly inhibited biofilm formation at concentrations >2 mg ml−1 (> 2000 μg ml−1), with bactericidal effects observed at concentrations of 8–64 mg ml−1 (8,000–64,000 μg ml−1). The authors suggested that the molecular mechanism driving the antibiotic-resistance was due to the expression of distinct bacterial genes such as mecA-, sea-, agrA-, and sarA, which was significantly reduced by A. princeps at >1 mg ml−1 (>1,000 μg ml−1) [40].

Another study assessed synergistic antimicrobial effects of aqueous and methanol extracts from Artemisia khorassanica and the antibiotics amikacin and imipenem, as a potential alternative treatment option of infections caused by MDR Acetinobacter baumannii [41]. The authors showed that, by suppressing the efflux pump activity via competitive and non-competitive inhibition, the methanol extracts were more effective than the aqueous extracts, given that in combination with amikacin and imipenem, the methanol extract decreased the MICs against different A. baumannii strains by 4- and 8-fold, while the aqueous extract resulted in 4-fold decreases. Additionally, the observed synergistic effect exerted by the methanol extract was hypothesized to be mediated by inhibiting the efflux pump activity through competitive or non-competitive inhibition rather than diminishing the expression of distinct efflux genes such as adeI and adeB [41].

Discussion

Summary

Since ancient times, secondary metabolites produced by medicinal plants have been widely applied to treat human diseases including infections [12, 42]. Additionally, the rapid emergence of MDR pathogens, partly due to improper use of antibiotics, is alarming and considered amongst the greatest challenges that the global healthcare systems have to face [12, 42]. As a result, finding new therapeutic approaches to combat the rise in drug resistance is urgent, particularly via agents that impede the antibiotic resistance mechanisms expressed by respective pathogens. Results of this literature survey demonstrate antibacterial activities for various compounds of several Artemisia species.

Some studies showed that the plant product exhibits a very low or even no antimicrobial activity when applied alone [28, 29, 31, 32, 39]. However, the products were synergistically active upon combination with established synthetic antibiotic drugs, even enhancing the efficacy of the tested antibiotics in some instances. These pronounced synergistic effects were observed in the combinations of artemisinin with metronidazole [30], petroleum and methanol ether extracts of A. annua with chloramphenicol [31], chrysosplentin, penduletin and chrysoeriol with norfloxacin, chrysoeriol with ciprofloxacin [39], extract of A. khorassanica with amikacin and imipenem [41] and the combination of DhL with chloramphenicol [38], for instance. Importantly, these results provide promising future options for the treatment of infectious diseases caused by MDR pathogens, whereby MDR strains of E. coli [32], A. baumanii [41], P. aeruginosa and K. pneumoniae [36, 38] and S. aureus [30, 39, 40] have become sensitive towards antibiotics when combined with the products derived from the Artemisia plants. In addition, some of the Artemisia compounds were equally potent as common antibiotics, as seen with artemisinin and artemisinic acid which are derived from A. annua, and were shown to exert antibiotic effects that were similar to those observed for clarithromycin against S. aureus and S. epidermidis [30], for instance. Moreover, the antibacterial effects of the plant extracts of A. annua and A. abyssinica on distinct Mycobacterium species, including M. tuberculosis and M. bovis, were virtually comparable to those observed upon application of synthetic antimycobacterial drugs [33, 34]. Some studies included in this survey revealed that the antibacterial effect of the plant product alone was even more pronounced when compared with established synthetic antibiotics. Among these highly potent plant products are the essential oils and to a smaller extent the ethanol extracts of the Artemisia plants. The antimicrobial potential of essential oils derived from A. annua and A. absinthium have been independently observed in two studies [43, 44]. Remarkably, the efficacy of the methanol ether extract of A. annua against E. coli and S. aureus [31] and that of the essential oil of A. annua against E. coli might be of pivotal clinical relevance, given that the antibacterial potency of the A. annua essential oil was comparable to the antibiotic effects exerted by 13 different synthetic antibiotics [32]. The pronounced antimicrobial effects of A. annua have been described before given its role in the treatment of malaria [45, 46]. Moreover, the essential oil of A. negrei was shown to be highly efficient when tested against MDR bacteria [36], which also held true for the ethanol extract of A. princeps [40] and the active agents eucalyptol and germacrene D, present in A. phaeolepis [37], and DhL found in A. douglasiana [38]. In fact, several studies indicated that the observed antibacterial effects can be traced back to the presence of monoterpenes and sesquiterpene lactones and possibly to a synergistic effect of the different phytocompounds present, which may explain the higher efficacy of essential oils compared to plant extracts or particularly active agents being tested. For that, we can assume that thujone, eucalyptol, germacrene D and DhL are particularly potent and promising for pharmacological use [36–38]. As a matter of fact, thujone constitutes a very important antimicrobial active agent, as it is present in many Artemisia species that exhibit antimicrobial activity (e.g. A. negrei, A. rupestris, A. phaeolepis, A. absinthium).

Some of the Artemisia species evaluated in our review have been examined in older publication. In a paper from 2002, for instance, Muyima et al. investigated the essential oil of A. afra as natural cosmetic preservative in aqueous cream formulations [47], whereas Setzer et al. addressed the antimicrobial activity of Artemisia douglasiana [48]. Furthermore, Nokerbek et al. reported potent antimicrobial effects of A. rupestris besides its cytotoxic and anticancer properties [49].

Conclusion and outlook

The here provided actual literature survey provides strong evidence that Artemisia plant products constitute promising antibacterial compounds that might be applied as “natural” alternatives to established synthetic antibiotics for the treatment of bacterial infections and as promising adjunct synergistic option to target MDR bacterial pathogens. Further investigations, particularly in vivo including clinical studies, are needed, however, to provide more robust evidence for antibacterial as well as immune-modulatory modes of action and prospective clinical application.

Limitations

Among the major limitations of this literature survey is the limited comparability of the studies included in this examination. The Artemisia species tested are numerous, although the species are similar in their phytocompounds; however, phytochemical analysis was not established in all of the investigations. In addition, the plant origins were different among studies, which in turn leads to a diverse phytochemical composition [50]. Moreover, the study designs including applied methods were different, whereby most of the studies investigated the methanol extract of the plant, but some also examined the aqueous extract, the ethanol extract, the hexane extract and the essential oil of the plant, for instance. Furthermore, another major limitation is that all included studies were in vitro investigations. Lastly, this literature survey was performed by one investigator only and thus, mistakes cannot be excluded. Therefore, the results need to be evaluated carefully.

Declarations

Ethics statement

Not applicable (literature survey).

Conflict of interests

SB and MMH are Editorial Board members.

Authors’ contributions

JJ conceived and designed the survey, wrote the paper. NWS co-wrote the paper. SB provided critical advice in design of the survey, edited the paper. MMH supervised the survey, co-wrote the paper.

References

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    World Health Organization . World antimicrobial awareness week. 2021 Sept. 17; Available from: https://www.who.int/campaigns/world-antimicrobial-awareness-week/2021.

    • Search Google Scholar
    • Export Citation
  • 2.

    Christaki E , Marcou M , Tofarides A . Antimicrobial resistance in bacteria: mechanisms, evolution, and persistence. J Mol Evol 2020;88(1):2640.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Antimicrobial Resistance Division . National action plans and monitoring and evaluation. In: Who library cataloguing-in-publication data, <global action plan on antimicrobial resistance.pdf>. World Health Organization, Editor; 2015. pp. 112.

    • Search Google Scholar
    • Export Citation
  • 4.

    D’Costa VM , King CE , Kalan L , Morar M , Sung WW , Schwarz C , et al. Antibiotic resistance is ancient. Nature 2011;477(7365):457461.

  • 5.

    Fleming A . Discovery and use of penicillin. Resen Clin Cient 1946;15:179186.

  • 6.

    Sandoval-Motta S , Aldana M . Adaptive resistance to antibiotics in bacteria: a systems biology perspective. Wiley Interdiscip Rev Syst Biol Med 2016;8(3):253267.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Fernandez L , Breidenstein EB , Hancock RE . Creeping baselines and adaptive resistance to antibiotics. Drug Resist Updat 2011;14(1):121.

  • 8.

    Levy SB , Marshall B . Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 2004;10(12):S122S129.

  • 9.

    Manyi-Loh C , Mamphweli S , Meyer E , Okoh A . Antibiotic use in agriculture and its consequential resistance in environmental sources: potential public health implications. Molecules 2018;23(4):795.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Harbarth S , Theuretzbacher U , Hackett J , consortium obotD -A , Adriaenssens N , Anderson J , et al. Antibiotic research and development: business as usual? J Antimicrob Chemother 2015;70(6):16041607.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Harbarth S , Balkhy HH , Goossens H , Jarlier V , Kluytmans J , Laxminarayan R , et al. Antimicrobial resistance: one world, one fight! Antimicrob Resist Infect Control 2015;4(1):49.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Martín J , Torrell M , Korobkov AA , Vallès J . Palynological features as a systematic marker in Artemisia L. and related genera (Asteraceae, Anthemideae) -II: implications for subtribe artemisiinae delimitation. Plant Biol 2003;5(1):8593.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Ekor M . The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol 2014;4:177–177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Bora KS , Sharma A . The genus Artemisia: a comprehensive review. Pharm Biol 2011;49(1):101109.

  • 15.

    Juteau F , Jerkovic I , Masotti V , Milos M , Mastelic J , Bessière JM , et al. Composition and antimicrobial activity of the essential oil of Artemisia absinthium from Croatia and France. Planta Med 2003;69(2):158161.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Robinson MM , Zhang X . The world medicines situation 2011 traditional medicines: global situation. Issues and Challenges; 2011.

  • 17.

    Balint GA . Artemisinin and its derivatives: an important new class of antimalarial agents. Pharmacol Ther 2001;90(2):261265.

  • 18.

    Arya A , Kojom Foko LP , Chaudhry S , Sharma A , Singh V . Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: a systematic review of clinical studies from two malaria endemic regions - India and sub-Saharan Africa. Int J Parasitol Drugs Drug Resist 2021;15:4356.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Dunay IR , Chan WC , Haynes RK , Sibley LD . Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. Antimicrob Agents Chemother 2009;53(10):44504456.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Mannan A , Ahmed I , Arshad W , Asim MF , Qureshi RA , Hussain I , et al. Survey of artemisinin production by diverse Artemisia species in northern Pakistan. Malar J 2010;9:310–310.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Efferth T . From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017;46:6583.

  • 22.

    Zheng GQ . Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60(1):5457.

  • 23.

    Tan RX , Zheng WF , Tang HQ . Biologically active substances from the genus Artemisia. Planta Med 1998;64(4):295302.

  • 24.

    Watson LE , Bates PL , Evans TM , Unwin MM , Estes JR . Molecular phylogeny of Subtribe Artemisiinae (Asteraceae), including Artemisia and its allied and segregate genera. BMC Evol Biol 2002;2(1):17.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Iranshahi M , Emami SA , Mahmoud-Soltani M . Detection of sesquiterpene lactones in ten Artemisia species population of Khorasan provinces. Iranian J Basic Med Sci 2007;10(3):183188.

    • Search Google Scholar
    • Export Citation
  • 26.

    Craciunescu O , Constantin D , Gaspar A , Toma L , Utoiu E , Moldovan L . Evaluation of antioxidant and cytoprotective activities of Arnica Montana L. and Artemisia absinthium L. ethanolic extracts. Chem Cent J 2012;6(1):97.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Charité Universitätsmedizin Berlin, Neufassung der Satzung der Charité – Universitätsmedizin Berlin zur Sicherung Guter Wissenschaftlicher Praxis vom 20.06.2012, in Amtliches Mitteilungsblatt. 2018: Berlin.17921800.

    • Search Google Scholar
    • Export Citation
  • 28.

    Khan MF , Tang H , Lyles JT , Pineau R , Mashwani ZU , Quave CL . Antibacterial properties of medicinal plants from Pakistan against multidrug-resistant ESKAPE pathogens. Front Pharmacol 2018;9:815.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Fiamegos YC , Kastritis PL , Exarchou V , Han H , Bonvin AM , Vervoort J , et al. Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against gram-positive pathogenic bacteria. PLoS One 2011;6(4), e18127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Goswami S , Bhakuni RS , Chinniah A , Pal A , Kar SK , Das PK . Anti-Helicobacter pylori potential of artemisinin and its derivatives. Antimicrob Agents Chemother 2012;56(9):45944607.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Rolta R , Sharma A , Sourirajan A , Mallikarjunan PK , Dev K . Combination between antibacterial and antifungal antibiotics with phytocompounds of Artemisia annua L: a strategy to control drug resistance pathogens. J Ethnopharmacol 2021;266:113420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Golbarg H , Mehdipour Moghaddam MJ . Antibacterial potency of medicinal plants including Artemisia annua and oxalis corniculata against multi-drug resistance. E. Coil Biomed Res Int 2021;2021:9981915.

    • Search Google Scholar
    • Export Citation
  • 33.

    Martini MC , Zhang T , Williams JT , Abramovitch RB , Weathers PJ , Shell SS . Artemisia annua and Artemisia afra extracts exhibit strong bactericidal activity against Mycobacterium Tuberculosis. J Ethnopharmacol 2020;262:113191.

    • Search Google Scholar
    • Export Citation
  • 34.

    Gemechu A , Giday M , Worku A , Ameni G . In vitro anti-mycobacterial activity of selected medicinal plants against Mycobacterium tuberculosis and Mycobacterium bovis strains. BMC Complement Altern Med 2013;13:291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Smirnova G , Samoilova Z , Muzyka N , Oktyabrsky O . Influence of plant polyphenols and medicinal plant extracts on antibiotic susceptibility of Escherichia coli. J Appl Microbiol 2012;113(1):192199.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Chebbac K , Moussaoui AE , Bourhia M , Salamatullah AM , Alzahrani A , Guemmouh R . Chemical analysis and antioxidant and antimicrobial activity of essential oils from Artemisia negrei L. Against drug-resistant microbes. Evid Based Complement Alternat Med 2021;2021:5902851.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Ben Hsouna A , Ben Halima N , Abdelkafi S , Hamdi N . Essential oil from Artemisia phaeolepis: chemical composition and antimicrobial activities. J Oleo Sci 2013;62(12):973980.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Mustafi S , Veisaga ML , Lopez LA , Barbieri MA . A novel insight into dehydroleucodine mediated attenuation of Pseudomonas aeruginosa virulence mechanism. Biomed Res Int 2015;2015:216097.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Lan JE , Li XJ , Zhu XF , Sun ZL , He JM , Zloh M , et al. Flavonoids from Artemisia rupestris and their synergistic antibacterial effects on drug-resistant Staphylococcus aureus. Nat Prod Res 2021;35(11):18811886.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Choi NY , Kang SY , Kim KJ . Artemisia princeps inhibits biofilm formation and virulence-factor expression of antibiotic-resistant bacteria. Biomed Res Int 2015;2015:239519.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Fatemi N , Sharifmoghadam MR , Bahreini M , Khameneh B , Shadifar H . Antibacterial and synergistic effects of herbal extracts in combination with amikacin and imipenem against multidrug-resistant isolates of acinetobacter. Curr Microbiol 2020;77(9):19591967.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Morteza-Semnani K , Saeedi M , Akbarzadeh M . Essential oil composition of Artemisia chamaemelifolia vill. J Essent Oil Res 2008;20(5):430431.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Joshi RK . Volatile composition and antimicrobial activity of the essential oil of Artemisia absinthium growing in Western Ghats region of North West Karnataka, India. Pharm Biol 2013;51(7):888892.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44.

    Marinas IC , Oprea E , Chifiriuc MC , Badea IA , Buleandra M , Lazar V . Chemical composition and antipathogenic activity of Artemisia annua essential oil from Romania. Chem Biodivers 2015;12(10):15541564.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Ramazani A , Sardari S , Zakeri S , Vaziri B . In vitro antiplasmodial and phytochemical study of five Artemisia species from Iran and in vivo activity of two species. Parasitol Res 2010;107(3):593599.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    Bilia AR , Santomauro F , Sacco C , Bergonzi MC , Donato R . Essential oil of Artemisia annua L.: an extraordinary component with numerous antimicrobial properties. Evid Based Complement Alternat Med 2014;2014:159819.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Muyima N , Zulu G , Bhengu T , Popplewell D . The potential application of some novel essential oils as natural cosmetic preservatives in a aqueous cream formulation. Flavour Fragrance J 2002;17:258266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48.

    Setzer WN , Vogler B , Schmidt JM , Leahy JG , Rives R . Antimicrobial activity of Artemisia douglasiana leaf essential oil. Fitoterapia 2004;75(2):192200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Nokerbek S , Sakipova Z , Chalupová M , Nejezchlebová M , Hošek J . Cytotoxic, anti-cancer, and anti-microbial effects of different extracts obtained from Artemisia rupestris. Ceska Slov Farm 2017;66(1):1522.

    • Search Google Scholar
    • Export Citation
  • 50.

    Zhang X , Zhao Y , Guo L , Qiu Z , Huang L , Qu X . Differences in chemical constituents of Artemisia annua L from different geographical regions in China. PLoS One 2017;12(9): e0183047.

    • Search Google Scholar
    • Export Citation
  • 1.

    World Health Organization . World antimicrobial awareness week. 2021 Sept. 17; Available from: https://www.who.int/campaigns/world-antimicrobial-awareness-week/2021.

    • Search Google Scholar
    • Export Citation
  • 2.

    Christaki E , Marcou M , Tofarides A . Antimicrobial resistance in bacteria: mechanisms, evolution, and persistence. J Mol Evol 2020;88(1):2640.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Antimicrobial Resistance Division . National action plans and monitoring and evaluation. In: Who library cataloguing-in-publication data, <global action plan on antimicrobial resistance.pdf>. World Health Organization, Editor; 2015. pp. 112.

    • Search Google Scholar
    • Export Citation
  • 4.

    D’Costa VM , King CE , Kalan L , Morar M , Sung WW , Schwarz C , et al. Antibiotic resistance is ancient. Nature 2011;477(7365):457461.

  • 5.

    Fleming A . Discovery and use of penicillin. Resen Clin Cient 1946;15:179186.

  • 6.

    Sandoval-Motta S , Aldana M . Adaptive resistance to antibiotics in bacteria: a systems biology perspective. Wiley Interdiscip Rev Syst Biol Med 2016;8(3):253267.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Fernandez L , Breidenstein EB , Hancock RE . Creeping baselines and adaptive resistance to antibiotics. Drug Resist Updat 2011;14(1):121.

  • 8.

    Levy SB , Marshall B . Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 2004;10(12):S122S129.

  • 9.

    Manyi-Loh C , Mamphweli S , Meyer E , Okoh A . Antibiotic use in agriculture and its consequential resistance in environmental sources: potential public health implications. Molecules 2018;23(4):795.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Harbarth S , Theuretzbacher U , Hackett J , consortium obotD -A , Adriaenssens N , Anderson J , et al. Antibiotic research and development: business as usual? J Antimicrob Chemother 2015;70(6):16041607.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Harbarth S , Balkhy HH , Goossens H , Jarlier V , Kluytmans J , Laxminarayan R , et al. Antimicrobial resistance: one world, one fight! Antimicrob Resist Infect Control 2015;4(1):49.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Martín J , Torrell M , Korobkov AA , Vallès J . Palynological features as a systematic marker in Artemisia L. and related genera (Asteraceae, Anthemideae) -II: implications for subtribe artemisiinae delimitation. Plant Biol 2003;5(1):8593.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Ekor M . The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol 2014;4:177–177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Bora KS , Sharma A . The genus Artemisia: a comprehensive review. Pharm Biol 2011;49(1):101109.

  • 15.

    Juteau F , Jerkovic I , Masotti V , Milos M , Mastelic J , Bessière JM , et al. Composition and antimicrobial activity of the essential oil of Artemisia absinthium from Croatia and France. Planta Med 2003;69(2):158161.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Robinson MM , Zhang X . The world medicines situation 2011 traditional medicines: global situation. Issues and Challenges; 2011.

  • 17.

    Balint GA . Artemisinin and its derivatives: an important new class of antimalarial agents. Pharmacol Ther 2001;90(2):261265.

  • 18.

    Arya A , Kojom Foko LP , Chaudhry S , Sharma A , Singh V . Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: a systematic review of clinical studies from two malaria endemic regions - India and sub-Saharan Africa. Int J Parasitol Drugs Drug Resist 2021;15:4356.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Dunay IR , Chan WC , Haynes RK , Sibley LD . Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. Antimicrob Agents Chemother 2009;53(10):44504456.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Mannan A , Ahmed I , Arshad W , Asim MF , Qureshi RA , Hussain I , et al. Survey of artemisinin production by diverse Artemisia species in northern Pakistan. Malar J 2010;9:310–310.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Efferth T . From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol 2017;46:6583.

  • 22.

    Zheng GQ . Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60(1):5457.

  • 23.

    Tan RX , Zheng WF , Tang HQ . Biologically active substances from the genus Artemisia. Planta Med 1998;64(4):295302.

  • 24.

    Watson LE , Bates PL , Evans TM , Unwin MM , Estes JR . Molecular phylogeny of Subtribe Artemisiinae (Asteraceae), including Artemisia and its allied and segregate genera. BMC Evol Biol 2002;2(1):17.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Iranshahi M , Emami SA , Mahmoud-Soltani M . Detection of sesquiterpene lactones in ten Artemisia species population of Khorasan provinces. Iranian J Basic Med Sci 2007;10(3):183188.

    • Search Google Scholar
    • Export Citation
  • 26.

    Craciunescu O , Constantin D , Gaspar A , Toma L , Utoiu E , Moldovan L . Evaluation of antioxidant and cytoprotective activities of Arnica Montana L. and Artemisia absinthium L. ethanolic extracts. Chem Cent J 2012;6(1):97.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Charité Universitätsmedizin Berlin, Neufassung der Satzung der Charité – Universitätsmedizin Berlin zur Sicherung Guter Wissenschaftlicher Praxis vom 20.06.2012, in Amtliches Mitteilungsblatt. 2018: Berlin.17921800.

    • Search Google Scholar
    • Export Citation
  • 28.

    Khan MF , Tang H , Lyles JT , Pineau R , Mashwani ZU , Quave CL . Antibacterial properties of medicinal plants from Pakistan against multidrug-resistant ESKAPE pathogens. Front Pharmacol 2018;9:815.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Fiamegos YC , Kastritis PL , Exarchou V , Han H , Bonvin AM , Vervoort J , et al. Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against gram-positive pathogenic bacteria. PLoS One 2011;6(4), e18127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Goswami S , Bhakuni RS , Chinniah A , Pal A , Kar SK , Das PK . Anti-Helicobacter pylori potential of artemisinin and its derivatives. Antimicrob Agents Chemother 2012;56(9):45944607.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Rolta R , Sharma A , Sourirajan A , Mallikarjunan PK , Dev K . Combination between antibacterial and antifungal antibiotics with phytocompounds of Artemisia annua L: a strategy to control drug resistance pathogens. J Ethnopharmacol 2021;266:113420.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Golbarg H , Mehdipour Moghaddam MJ . Antibacterial potency of medicinal plants including Artemisia annua and oxalis corniculata against multi-drug resistance. E. Coil Biomed Res Int 2021;2021:9981915.

    • Search Google Scholar
    • Export Citation
  • 33.

    Martini MC , Zhang T , Williams JT , Abramovitch RB , Weathers PJ , Shell SS . Artemisia annua and Artemisia afra extracts exhibit strong bactericidal activity against Mycobacterium Tuberculosis. J Ethnopharmacol 2020;262:113191.

    • Search Google Scholar
    • Export Citation
  • 34.

    Gemechu A , Giday M , Worku A , Ameni G . In vitro anti-mycobacterial activity of selected medicinal plants against Mycobacterium tuberculosis and Mycobacterium bovis strains. BMC Complement Altern Med 2013;13:291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Smirnova G , Samoilova Z , Muzyka N , Oktyabrsky O . Influence of plant polyphenols and medicinal plant extracts on antibiotic susceptibility of Escherichia coli. J Appl Microbiol 2012;113(1):192199.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Chebbac K , Moussaoui AE , Bourhia M , Salamatullah AM , Alzahrani A , Guemmouh R . Chemical analysis and antioxidant and antimicrobial activity of essential oils from Artemisia negrei L. Against drug-resistant microbes. Evid Based Complement Alternat Med 2021;2021:5902851.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Ben Hsouna A , Ben Halima N , Abdelkafi S , Hamdi N . Essential oil from Artemisia phaeolepis: chemical composition and antimicrobial activities. J Oleo Sci 2013;62(12):973980.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    Mustafi S , Veisaga ML , Lopez LA , Barbieri MA . A novel insight into dehydroleucodine mediated attenuation of Pseudomonas aeruginosa virulence mechanism. Biomed Res Int 2015;2015:216097.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Lan JE , Li XJ , Zhu XF , Sun ZL , He JM , Zloh M , et al. Flavonoids from Artemisia rupestris and their synergistic antibacterial effects on drug-resistant Staphylococcus aureus. Nat Prod Res 2021;35(11):18811886.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Choi NY , Kang SY , Kim KJ . Artemisia princeps inhibits biofilm formation and virulence-factor expression of antibiotic-resistant bacteria. Biomed Res Int 2015;2015:239519.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Fatemi N , Sharifmoghadam MR , Bahreini M , Khameneh B , Shadifar H . Antibacterial and synergistic effects of herbal extracts in combination with amikacin and imipenem against multidrug-resistant isolates of acinetobacter. Curr Microbiol 2020;77(9):19591967.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Morteza-Semnani K , Saeedi M , Akbarzadeh M . Essential oil composition of Artemisia chamaemelifolia vill. J Essent Oil Res 2008;20(5):430431.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Joshi RK . Volatile composition and antimicrobial activity of the essential oil of Artemisia absinthium growing in Western Ghats region of North West Karnataka, India. Pharm Biol 2013;51(7):888892.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44.

    Marinas IC , Oprea E , Chifiriuc MC , Badea IA , Buleandra M , Lazar V . Chemical composition and antipathogenic activity of Artemisia annua essential oil from Romania. Chem Biodivers 2015;12(10):15541564.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Ramazani A , Sardari S , Zakeri S , Vaziri B . In vitro antiplasmodial and phytochemical study of five Artemisia species from Iran and in vivo activity of two species. Parasitol Res 2010;107(3):593599.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    Bilia AR , Santomauro F , Sacco C , Bergonzi MC , Donato R . Essential oil of Artemisia annua L.: an extraordinary component with numerous antimicrobial properties. Evid Based Complement Alternat Med 2014;2014:159819.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Muyima N , Zulu G , Bhengu T , Popplewell D . The potential application of some novel essential oils as natural cosmetic preservatives in a aqueous cream formulation. Flavour Fragrance J 2002;17:258266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48.

    Setzer WN , Vogler B , Schmidt JM , Leahy JG , Rives R . Antimicrobial activity of Artemisia douglasiana leaf essential oil. Fitoterapia 2004;75(2):192200.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Nokerbek S , Sakipova Z , Chalupová M , Nejezchlebová M , Hošek J . Cytotoxic, anti-cancer, and anti-microbial effects of different extracts obtained from Artemisia rupestris. Ceska Slov Farm 2017;66(1):1522.

    • Search Google Scholar
    • Export Citation
  • 50.

    Zhang X , Zhao Y , Guo L , Qiu Z , Huang L , Qu X . Differences in chemical constituents of Artemisia annua L from different geographical regions in China. PLoS One 2017;12(9): e0183047.

    • Search Google Scholar
    • Export Citation
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The author instruction is available in PDF.
Please, download the file from HERE.
 

Senior editors

Editor(s)-in-Chief: Dunay, Ildiko Rita

Editor(s)-in-Chief: Heimesaat, Markus M.

Vice Editor(s)-in-Chief: Fuchs, Anja

Editorial Board

Chair of the Editorial Board:
Jeffrey S. Buguliskis (Thomas Jefferson University, USA)

  • Jörn Albring (University of Münster, Germany)
  • Stefan Bereswill (Charité - University Medicine Berlin, Germany)
  • Dunja Bruder (University of Megdeburg, Germany)
  • Jan Buer (University of Duisburg, Germany)
  • Jeff Buguliskis (Thomas Jefferson University, USA)
  • Edit Buzas (Semmelweis University, Hungary)
  • Charles Collyer (University of Sydney, Australia)
  • Renato Damatta (UENF, Brazil)
  • Ivelina Damjanova (Semmelweis University, Hungary)
  • Maria Deli (Biological Research Center, HAS, Hungary)
  • Olgica Djurković-Djaković (University of Belgrade, Serbia)
  • Jean-Dennis Docquier (University of Siena, Italy)
  • Anna Erdei (Eötvös Loránd University, Hungary)
  • Zsuzsanna Fabry (University of Washington, USA)
  • Beniam Ghebremedhin (Witten/Herdecke University, Germany)
  • Nancy Guillen (Institute Pasteur, France)
  • Georgina L. Hold (University of Aberdeen, United Kingdom)
  • Ralf Ignatius (Charité - University Medicine Berlin, Germany)
  • Zsuzsanna Izsvak (MDC-Berlin, Germany)
  • Achim Kaasch (University of Cologne, Germany)
  • Tamás Laskay (University of Lübeck, Germany)
  • Oliver Liesenfeld (Roche, USA)
  • Shreemanta Parida (Vaccine Grand Challenge Program, India)
  • Matyas Sandor (University of Wisconsin, USA)
  • Ulrich Steinhoff (University of Marburg, Germany)
  • Michal Toborek (University of Miami, USA)
  • Mary Jo Wick (University of Gothenburg, Sweden)
  • Susanne A. Wolf (MDC-Berlin, Germany)

 

Dr. Dunay, Ildiko Rita
Magdeburg, Germany
E-mail: ildikodunay@gmail.com

Indexing and Abstracting Services:

  • PubMed Central
  • Scopus
  • ESCI
  • CABI

 

2021  
Web of Science  
Total Cites
WoS
790
Journal Impact Factor not applicable
Rank by Impact Factor not applicable
Impact Factor
without
Journal Self Cites
not applicable
5 Year
Impact Factor
not applicable
Journal Citation Indicator 0,64
Rank by Journal Citation Indicator Microbiology 81/157
Scimago  
Scimago
H-index
not indexed
Scimago
Journal Rank
not indexed
Scimago Quartile Score not indexed
Scopus  
Scopus
Cite Score
not indexed
Scopus
CIte Score Rank
  not indexed
Scopus
SNIP
not indexed

2020  
CrossRef Documents 23
WoS Cites 708
Wos H-index 27
Days from submission to acceptance 219
Days from acceptance to publication 176
Acceptance Rate 70%

2019  
WoS
Cites
558
CrossRef
Documents
24
Acceptance
Rate
92%

 

European Journal of Microbiology and Immunology
Publication Model Gold Open Access
Submission Fee none
Article Processing Charge 600 EUR/article
Regional discounts on country of the funding agency World Bank Lower-middle-income economies: 50%
World Bank Low-income economies: 100%
Further Discounts Editorial Board / Advisory Board members: 50%
Corresponding authors, affiliated to an EISZ member institution subscribing to the journal package of Akadémiai Kiadó: 100%
Subscription Information Gold Open Access
Purchase per Title  

European Journal of Microbiology and Immunology
Language English
Size A4
Year of
Foundation
2011
Volumes
per Year
1
Issues
per Year
4
Founder Akadémiai Kiadó
Founder's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2062-509X (Print)
ISSN 2062-8633 (Online)

Monthly Content Usage

Abstract Views Full Text Views PDF Downloads
Mar 2022 0 0 0
Apr 2022 0 189 107
May 2022 0 216 129
Jun 2022 0 89 64
Jul 2022 0 82 36
Aug 2022 0 49 17
Sep 2022 0 0 0