title: Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens.
abstract: Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant A. baumannii. Recent reports of polymyxin-resistant A. baumannii highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in A. baumannii AB307-0294 using an in vitro dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log10CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens; partial reversion to susceptibility was observed in 6 of 8 bacterial samples during drug-free passaging. Stable polymyxin-resistant samples contained a mutation in pmrB. The transcriptomes of stable and non-stable polymyxin-resistant samples were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported via integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Soon-Ee
authors.initials: SE
authors.lastname: Cheah
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University of Buffalo, Kapoor Hall, Buffalo, NY 14214-8033, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, Department of Pharmacy Practice, University of Buffalo, Kapoor Hall, Buffalo, NY 14214-8033, USA.|Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill NC 27599, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.|Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, 6550 Sanger Road, Orloando FL 32827, USA.
authors.forename: Jurgen B
authors.initials: JB
authors.lastname: Bulitta
authors.affiliation: Biomedicine Discovery Institute and Department of Microbiology, School of Biomedical Sciences, Monash University (Clayton campus), Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Boyce
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000151:Acinetobacter Infections / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D015169:Colony Count, Microbial; D024881:Drug Resistance, Bacterial; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D023281:Genomics; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D011113:Polymyxins / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C409039:PmrB protein, bacteria; D011113:Polymyxins; D014157:Transcription Factors