Colistin is one of the last remaining active antibiotics against multidrug resistant Gram-negative bacteria. However, several recent studies reported colistin-resistant (ColR) Acinetobacter baumannii from different countries. In the current study, we investigated molecular mechanisms involved in colistin resistance in A. baumannii isolates from different clinical samples.
A total of 110 clinical A. baumannii isolates were collected from two hospitals in Tehran. Minimum inhibitory concentrations (MICs) were determined by broth microdilution according to the Clinical and Laboratory Standards Institute. For the ColR isolates, mutation was detected in pmrA, pmrB, lpxA, lpxC, and lpxD genes using the polymerase chain reaction (PCR) and sequencing. Moreover, the relative expression of the pmrC gene was calculated using quantitative reverse transcription PCR. Three colistin resistant isolates were identified with MIC between 8 and 16 μg/mL and were resistant to all the tested antimicrobial agents. All the three isolates had a mutation in the pmrB, pmrA, lpxA, lpxD, and lpxC genes. Moreover, the overexpression of pmrC gene was observed in all isolates. Our results showed that the upregulation of the PmrAB two component system was the primary mechanism linked to colistin resistance among the studied colistin resistant A. baumannii isolates.
Moffatt JH , Harper M , Harrison P , Hale JD , Vinogradov E , Seemann T , et al.. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother 2010; 54(12): 4971–4977.
Peleg AY , Seifert H , Paterson DL . Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 2008; 21(3): 538–582.
Qureshi ZA , Hittle LE , O’Hara JA , Rivera JI , Syed A , Shields RK , et al.. Colistin-resistant Acinetobacter baumannii: beyond carbapenem resistance. Clin Infect Dis 2015; 60(9): 1295–1303.
Li J , Nation RL , Turnidge JD , Milne RW , Coulthard K , Rayner CR , et al.. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 2006; 6(9): 589–601.
Conly J , Johnston B . Colistin: the phoenix arises. Can J Infect Dis Med Microbiol 2006: 17.
Deris ZZ , Swarbrick JD , Roberts KD , Azad MA , Akter J , Horne AS , et al.. Probing the penetration of antimicrobial polymyxin lipopeptides into gram-negative bacteria. Bioconjug Chem 2014; 25(4): 750–760.
Adams MD , Nickel GC , Bajaksouzian S , Lavender H , Murthy AR , Jacobs MR , et al.. Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component system. Antimicrob Agents Chemother 2009; 53(9): 3628–3634.
Lesho E , Yoon E-J , McGann P , Snesrud E , Kwak Y , Milillo M , et al.. Emergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections. J Infect Dis 2013; 208(7): 1142–1151.
Jeannot K , Bolard A , Plesiat P . Resistance to polymyxins in Gram-negative organisms. Int J Antimicrob Agents 2017; 49(5): 526–535.
Olaitan AO , Morand S , Rolain J-M . Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol 2014; 5: 643.
Tamayo R , Choudhury B , Septer A , Merighi M , Carlson R , Gunn J . Identification of cptA, a PmrA-regulated locus required for phosphoethanolamine modification of the Salmonella enterica serovar typhimurium lipopolysaccharide core. J Bacteriol 2005; 187(10): 3391–3399.
Lean S-S , Suhaili Z , Ismail S , Rahman NIA , Othman N , Abdullah FH , et al.. Prevalence and genetic characterization of carbapenem-and polymyxin-resistant Acinetobacter baumannii isolated from a tertiary hospital in Terengganu, Malaysia. Inter. Sch. Res. Notices 2014;2014.
Andrade FF , Silva D , Rodrigues A , Pina-Vaz C . Colistin update on its mechanism of action and resistance, present and future challenges. Microorganisms 2020; 8(11): 1716.
Haeili M , Kafshdouz M , Feizabadi MM . Molecular mechanisms of colistin resistance among pandrug-resistant isolates of Acinetobacter baumannii with high case-fatality rate in intensive care unit patients. Microb Drug Resist 2018; 24(9): 1271–1276.
Clinical and Laboratory Standards Institute . Performance standards for antimicrobial susceptibility testing. Wayne, PA: Clinical and Laboratory Standards Institute; 2020.
Magiorakos A-P , Srinivasan A , Carey R , Carmeli Y , Falagas M , Giske C , et al.. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18(3): 268–281.
Wiegand I , Hilpert K , Hancock RE . Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc 2008; 3(2): 163.
Haeili M , Javani A , Moradi J , Jafari Z , Feizabadi MM , Babaei E . MgrB alterations mediate colistin resistance in Klebsiella pneumoniae isolates from Iran. Front Microbiol 2017; 8: 2470.
Pourhajibagher M , Mokhtaran M , Esmaeili D , Bahador A . Antibiotic resistance patterns among Acinetobacter baumannii strains isolated from burned patients. 2016.
Livak KJ , Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods 2001; 25(4): 402–408.
Turton JF , Woodford N , Glover J , Yarde S , Kaufmann ME , Pitt TL . Identification of Acinetobacter baumannii by detection of the blaOXA-51-like carbapenemase gene intrinsic to this species. J Clin Microbiol 2006; 44(8): 2974–2976.
Peleg AY , Adams J , Paterson DL . Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii. Antimicrob Agents Chemother 2007; 51(6): 2065–2069.
Cai Y , Chai D , Wang R , Liang B , Bai N . Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies. J Antimicrob Chemother 2012; 67(7): 1607–1615.
Hejnar P , Kolář M , Hájek V . Characteristics of Acinetobacter strains (phenotype classification, antibiotic susceptibility and production of ss-lactamases) isolated from haemocultures from patients at the Teaching Hospital in Olomouc. Biomed Papers 1999.
Marinelli F , Antimicrobials Genilloud O. : New and Old Molecules in the fight against multi-resistant bacteria: Springer science & business media; 2013.
Pormohammad A , Mehdinejadiani K , Gholizadeh P , Nasiri MJ , Mohtavinejad N , Dadashi M , et al.. Global prevalence of colistin resistance in clinical isolates of Acinetobacter baumannii: a systematic review and meta-analysis. Microb Pathogenesis 2020; 139: 103887.
Ezadi F , Jamali A , Heidari A , Javid N , Ardebili A . Heteroresistance to colistin in oxacillinase-producing carbapenem-resistant Acinetobacter baumannii clinical isolates from Gorgan, Northern Iran. J Glob Antimicrob Resist 2020; 21: 380–385.
Beceiro A , Llobet E , Aranda J , Bengoechea JA , Doumith M , Hornsey M , et al.. Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother 2011; 55(7): 3370–3379.
Park YK , Choi JY , Shin D , Ko KS . Correlation between overexpression and amino acid substitution of the PmrAB locus and colistin resistance in Acinetobacter baumannii. Int J Antimicrob Agents 2011; 37(6): 525–530.