Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens

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.

• Publication year

  2016

• Venue

  Scientific Reports

• Publication date

  2016-05-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/srep26233PMID 27195897PMCID 4872528
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

  2015cited by this paper
• The transcriptomic response of Acinetobacter baumannii to colistin and doripenem alone and in combination in an in vitro pharmacokinetics/pharmacodynamics model.

  2015cited by this paper
• A PmrB-Regulated Deacetylase Required for Lipid A Modification and Polymyxin Resistance in Acinetobacter baumannii

  2015cited by this paper
• Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus.

  2015cited by this paper
• limma powers differential expression analyses for RNA-sequencing and microarray studies

  2015cited by this paper
• Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two 'old' antibiotics-polymyxin B and chloramphenicol.

  2015cited by this paper
• Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

  2014cited by this paper
• Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model.

  2014cited by this paper
• Colistin and polymyxin B: peas in a pod, or chalk and cheese?

  2014cited by this paper
• Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalized in intensive care units in United States and European hospitals (2009-2011).

  2014cited by this paper
• InterProScan 5: genome-scale protein function classification

  2014cited by this paper
• Susceptibility rates in Latin American nations: report from a regional resistance surveillance program (2011)

  2013cited by this paper
• Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens.

  2013cited by this paper
• A secondary mode of action of polymyxins against Gram-negative bacteria involves the inhibition of NADH-quinone oxidoreductase activity

  2013cited by this paper
• Characteristics of carbapenem-resistant Enterobacteriaceae isolates from Korea.

  2013cited by this paper
• Antimicrobial susceptibility of 22746 pathogens from Canadian hospitals: results of the CANWARD 2007-11 study.

  2013cited by this paper
• Application of a Loading Dose of Colistin Methanesulfonate in Critically Ill Patients: Population Pharmacokinetics, Protein Binding, and Prediction of Bacterial Kill

  2012cited by this paper
• The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model

  2012cited by this paper
• Rapid Killing of Acinetobacter baumannii by Polymyxins Is Mediated by a Hydroxyl Radical Death Pathway

  2012cited by this paper
• Antimicrobial resistance among Gram-negative bacilli isolated from Latin America: results from SENTRY Antimicrobial Surveillance Program (Latin America, 2008-2010).

  2012cited by this paper
• Haplotype-based variant detection from short-read sequencing

  2012cited by this paper
• Insertion Sequence ISAba11 Is Involved in Colistin Resistance and Loss of Lipopolysaccharide in Acinetobacter baumannii

  2011cited by this paper
• The pmrCAB Operon Mediates Polymyxin Resistance in Acinetobacter baumannii ATCC 17978 and Clinical Isolates through Phosphoethanolamine Modification of Lipid A

  2011cited by this paper
• Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems

  2011cited by this paper
• Saturability of Granulocyte Kill of Pseudomonas aeruginosa in a Murine Model of Pneumonia

  2011cited by this paper
• Correlation between overexpression and amino acid substitution of the PmrAB locus and colistin resistance in Acinetobacter baumannii.

  2011cited by this paper
• Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

  2011cited by this paper
• Structure--activity relationships of polymyxin antibiotics.

  2010cited by this paper
• Resistance to polymyxins: Mechanisms, frequency and treatment options.

  2010cited by this paper
• The Population Structure of Acinetobacter baumannii: Expanding Multiresistant Clones from an Ancestral Susceptible Genetic Pool

  2010cited by this paper
• Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production

  2010cited by this paper
• Resistance to Colistin in Acinetobacter baumannii Associated with Mutations in the PmrAB Two-Component System

  2009cited by this paper
• Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

  2009cited by this paper
• Colistin in the 21st century

  2009cited by this paper
• Looming Global-Scale Failures and Missing Institutions

  2009cited by this paper
• Acinetobacter baumannii: Emergence of a Successful Pathogen

  2008cited by this paper
• Interscience Conference on Antimicrobial Agents and Chemotherapy

  2008cited by this paper
• Comparison of once-, twice- and thrice-daily dosing of colistin on antibacterial effect and emergence of resistance: studies with Pseudomonas aeruginosa in an in vitro pharmacodynamic model.

  2008cited by this paper
• Comparative Genome Sequence Analysis of Multidrug-Resistant Acinetobacter baumannii

  2008cited by this paper
• Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review.

  2007cited by this paper
• Alternative mechanisms of action of cationic antimicrobial peptides on bacteria

  2007cited by this paper
• Antibiograms of multidrug-resistant clinical Acinetobacter baumannii: promising therapeutic options for treatment of infection with colistin-resistant strains.

  2007cited by this paper
• OrthoMCL: identification of ortholog groups for eukaryotic genomes.

  2003cited by this paper
• Inorganic polyphosphate is essential for long-term survival and virulence factors in Shigella and Salmonella spp.

  2002cited by this paper
• Contemporary Assessment of Antimicrobial Susceptibility Testing Methods for Polymyxin B and Colistin: Review of Available Interpretative Criteria and Quality Control Guidelines

  2001cited by this paper
• Interactions of Bacterial Cationic Peptide Antibiotics with Outer and Cytoplasmic Membranes ofPseudomonas aeruginosa

  2000cited by this paper
• Peptide Antibiotics

  1999cited by this paper
• Peptide antibiotics.

  1997cited by this paper
• Controlling the false discovery rate: a practical and powerful approach to multiple testing

  1995cited by this paper

• Turning the Tide Against Carbapenem-resistant Acinetobacter baumannii: Advancing Care With Sulbactam–Durlobactam

  2025cites this paper
• Mutations in two-component signaling systems drive experimental evolution of tigecycline and colistin resistance in Acinetobacter baumannii

  2025cites this paper
• Molecular insights into silver nanoparticle resistance in Acinetobacter baumannii and unique adaptations to ionic silver

  2025cites this paper
• Antibacterial activity of enmetazobactam against Acinetobacter spp.: a molecular dissection of mechanism of action and resistance determinants

  2025cites this paper
• Unveiling the role of BON domain-containing proteins in antibiotic resistance

  2025cites this paper
• Exploring the occurrence of Pseudomonas aeruginosa and comprehensive whole genome analysis of the bcsir_p4_s20 strain from municipal wastewater in Chattogram

  2025cites this paper
• Acinetobacter baumannii: Mechanisms of Antimicrobial Resistance

  2025cites this paper
• Paeonol potentiates colistin efficacy against K. pneumoniae by promoting membrane disruption and oxidative damage.

  2024cites this paper
• Deciphering Antibiotic-Targeted Metabolic Pathways in Acinetobacter baumannii: Insights from Transcriptomics and Genome-Scale Metabolic Modeling

  2024cites this paper
• Polymyxins: recent advances and challenges

  2024cites this paper
• Transcriptomic investigations of polymyxins and colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii

  2024cites this paper
• A molecular overview of the polymyxin-LPS interaction in the context of its mode of action and resistance development.

  2024cites this paper
• Colistin Resistance Mechanism and Management Strategies of Colistin-Resistant Acinetobacter baumannii Infections

  2024cites this paper
• Metabolic profiling unveils enhanced antibacterial synergy of polymyxin B and teixobactin against multi-drug resistant Acinetobacter baumannii

  2024cites this paper
• Carbonyl Cyanide 3-Chloro Phenyl Hydrazone (CCCP) Restores the Colistin Sensitivity in Brucella intermedia

  2023cites this paper
• Beyond the identifiable proteome: Delving into the proteomics of polymyxin-resistant and non-resistant Acinetobacter baumannii from Brazilian hospitals.

  2023cites this paper
• Role of efflux pumps, their inhibitors, and regulators in colistin resistance

  2023cites this paper
• Model-Informed Dose Optimisation of Polymyxin-Rifampicin Combination Therapy against Multidrug-Resistant Acinetobacter baumannii.

  2023cites this paper
• Drug Combination of Ciprofloxacin and Polymyxin B for the Treatment of Multidrug–Resistant Acinetobacter baumannii Infections: A Drug Pair Limiting the Development of Resistance

  2023cites this paper
• Whole genome sequencing of the multidrug-resistant Chryseobacterium indologenes isolated from a patient in Brazil

  2022cites this paper
• Carbapenem-resistant Acinetobacter baumannii: A challenge in the intensive care unit

  2022cites this paper
• Integrated metabolomic and transcriptomic analyses of the synergistic effect of polymyxin–rifampicin combination against Pseudomonas aeruginosa

  2022cites this paper
• Rapid evolution of colistin resistance in a bioreactor model of infection of Klebsiella pneumoniae

  2022cites this paper
• Constitutive Phenotypic Modification of Lipid A in Clinical Acinetobacter baumannii Isolates

  2022cites this paper
• Infections Due to Acinetobacter baumannii-calcoaceticus Complex: Escalation of Antimicrobial Resistance and Evolving Treatment Options.

  2022cites this paper
• Whole-Genome Sequencing of a Colistin-Resistant Acinetobacter baumannii Strain Isolated at a Tertiary Health Facility in Pretoria, South Africa

  2022cites this paper
• Exogenous metabolite feeding on altering antibiotic susceptibility in Gram-negative bacteria through metabolic modulation: a review

  2022cites this paper
• Insights into collateral susceptibility and collateral resistance in Acinetobacter baumannii during antimicrobial adaptation

  2021cites this paper
• Relationship between L-lactate dehydrogenase and multidrug resistance in Staphylococcus xylosus

  2021cites this paper
• Mining for encrypted peptide antibiotics in the human proteome

  2021cites this paper
• Structure of the Acinetobacter baumannii PmrA receiver domain and insights into clinical mutants affecting DNA-binding and promoting colistin resistance.

  2021cites this paper
• Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria

  2021cites this paper
• A review on new aspects of lipopeptide biosurfactant: Types, production, properties and its application in the bioremediation process.

  2020cites this paper
• Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

  2020cites this paper
• Regulating polymyxin resistance in Gram-negative bacteria: roles of two-component systems PhoPQ and PmrAB.

  2020cites this paper
• Acquisition of Colistin Resistance Links Cell Membrane Thickness Alteration with a Point Mutation in the lpxD Gene in Acinetobacter baumannii

  2020cites this paper
• Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019)

  2020cites this paper
• In vitro and in vivo efficacy of combinations of colistin and different endolysins against clinical strains of multi-drug resistant pathogens

  2020cites this paper
• Pan-transcriptomic analysis identified common differentially expressed genes of Acinetobacter baumannii in response to polymyxin treatments.

  2020cites this paper
• Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing

  2020cites this paper
• Polymyxins Bind to the Cell Surface of Unculturable Acinetobacter baumannii and Cause Unique Dependent Resistance

  2020cites this paper
• BonA from Acinetobacter baumannii Forms a Divisome-Localized Decamer That Supports Outer Envelope Function

  2020cites this paper
• Novel antimicrobial development using genome-scale metabolic model of Gram-negative pathogens: a review

  2020cites this paper
• Agents of Last Resort: An Update on Polymyxin Resistance.

  2020cites this paper
• Combatting The Rising Tide of Antimicrobial Resistance: Pharmacokinetic/Pharmacodynamic Dosing Strategies for Maximal Precision.

  2020cites this paper
• Detection of multidrug resistant environmental isolates of acinetobacter and Stenotrophomonas maltophilia: a possible threat for community acquired infections?

  2020cites this paper
• Molecular mechanisms of polymyxin resistance and detection of mcr genes.

  2019cites this paper
• Darwinian selection analysis of the two-component system PmrAB indicates there could be lingering delay in emergence of colistin resistance in Acinetobacter baumannii

  2019cites this paper
• Paucity of adaptive selection in PmrAB two-component system may resist emergence of colistin resistance in Acinetobacter baumannii

  2019cites this paper
• In vitro and in vivo efficacy of the combination of colistin and endolysins against clinical strains of Multi-Drug Resistant (MDR) pathogens

  2019cites this paper
• Evaluation of SNP calling methods for closely related bacterial isolates and a novel high-accuracy pipeline: BactSNP

  2019cites this paper
• Polymyxins interaction to the human serum albumin: A thermodynamic and computational study.

  2019cites this paper
• Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii

  2019cites this paper
• Metabolic Responses to Polymyxin Treatment in Acinetobacter baumannii ATCC 19606: Integrating Transcriptomics and Metabolomics with Genome-Scale Metabolic Modeling

  2019cites this paper
• Colistin Resistant A. baumannii: Genomic and Transcriptomic Traits Acquired Under Colistin Therapy

  2019cites this paper
• Expanding the paradigm for the outer membrane: Acinetobacter baumannii in the absence of endotoxin

  2018cites this paper
• Contribution of efflux to colistin heteroresistance in a multidrug resistant Acinetobacter baumannii clinical isolate

  2018cites this paper
• Colistin Heteroresistance and Involvement of the PmrAB Regulatory System in Acinetobacter baumannii

  2018cites this paper
• Achieving a Predictive Understanding of Antimicrobial Stress Physiology through Systems Biology.

  2018cites this paper
• Colistin Resistance in Acinetobacter baumannii MDR-ZJ06 Revealed by a Multiomics Approach

  2017influential citation
• Recent advances and perspectives in the design and development of polymyxins.

  2017cites this paper
• Potent β-Lactam Enhancer Activity of Zidebactam and WCK 5153 against Acinetobacter baumannii, Including Carbapenemase-Producing Clinical Isolates

  2017cites this paper
• An allelic variant of the PmrB sensor kinase responsible for colistin resistance in an Escherichia coli strain of clinical origin

  2017cites this paper
• Pharmacodynamics of dose-escalated ‘front-loading’ polymyxin B regimens against polymyxin-resistant mcr-1-harbouring Escherichia coli

  2017cites this paper
• Transcriptome Remodeling of Acinetobacter baumannii during Infection and Treatment

  2017cites this paper
• Resistance to polymyxins in Gram-negative organisms.

  2017cites this paper
• The secondary resistome of multidrug-resistant Klebsiella pneumoniae

  2017cites this paper
• Infections Due to Acinetobacter baumannii in the ICU: Treatment Options

  2017cites this paper
• Tracking Cefoperazone/Sulbactam Resistance Development In vivo in A. baumannii Isolated from a Patient with Hospital-Acquired Pneumonia by Whole-Genome Sequencing

  2016cites this paper
• On the path to untreatable infections: colistin use in agriculture and the end of ‘last resort’ antibiotics

  2016cites this paper