ArticleThe Journal of antimicrobial chemotherapy2019
Polymyxin resistance in Klebsiella pneumoniae: multifaceted mechanisms utilized in the presence and absence of the plasmid-encoded phosphoethanolamine transferase gene mcr-1.
Article in The Journal of antimicrobial chemotherapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- Klebsiella pneumoniae in the global AMR: resistance mechanisms and genomic adaptation.World journal of microbiology & biotechnology · 2026Review
- Resensitizing the Untreatable: Zidovudine and Polymyxin Combinations to Combat Pan-Drug-ResistantPharmaceuticals (Basel, Switzerland) · 2025Article
- Emergence of drug-resistantMicrobiology spectrum · 2025Article
- Article
- Highlighting the Potential of LyeTx I, a Peptide Derived from the Venom of the SpiderPharmaceuticals (Basel, Switzerland) · 2025Article
- Polyproline peptide targetsCell reports. Physical science · 2024Article
- Lipid A Modification and Metabolic Adaptation in Polymyxin-Resistant, New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae.Microbiology spectrum · 2023Article
- Modulation ofBiomedicines · 2023Article
- First Belgian Report of Ertapenem Resistance in an ST11Antibiotics (Basel, Switzerland) · 2022Article
- Genetic Diversity of Virulent Polymyxin-ResistantAntibiotics (Basel, Switzerland) · 2022Article
- Comparative metabolomics revealed key pathways associated with the synergistic killing of multidrug-resistantComputational and structural biotechnology journal · 2022Article
- Cell Membrane Remodeling Mediates Polymyxin B Resistance inFrontiers in microbiology · 2022Article
- Clinical Perspective of Antimicrobial Resistance in Bacteria.Infection and drug resistance · 2022Review
- Whole Genome Sequencing of PediatricFrontiers in microbiology · 2021Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
objectivesUntil plasmid-mediated mcr-1 was discovered, it was believed that polymyxin resistance in Gram-negative bacteria was mainly mediated by the chromosomally-encoded EptA and ArnT, which modify lipid A with phosphoethanolamine (pEtN) and 4-amino-4-deoxy-l-arabinose (l-Ara4N), respectively. This study aimed to construct a markerless mcr-1 deletion mutant in Klebsiella pneumoniae, validate a reliable reference gene for reverse transcription quantitative PCR (RT-qPCR) and investigate the interactions among mcr-1, arnT and eptA, in response to polymyxin treatments using pharmacokinetics/pharmacodynamics (PK/PD).
methodsAn isogenic markerless mcr-1 deletion mutant (II-503Δmcr-1) was generated from a clinical K. pneumoniae II-503 isolate. The efficacy of different polymyxin B dosage regimens was examined using an in vitro one-compartment PK/PD model and polymyxin resistance was assessed using population analysis profiles. The expression of mcr-1, eptA and arnT was examined using RT-qPCR with a reference gene pepQ, and lipid A was profiled using LC-MS. In vivo polymyxin B efficacy was investigated in a mouse thigh infection model.
resultsIn K. pneumoniae II-503, mcr-1 was constitutively expressed, irrespective of polymyxin exposure. Against II-503Δmcr-1, an initial bactericidal effect was observed within 4 h with polymyxin B at average steady-state concentrations of 1 and 3 mg/L, mimicking patient PK. However, substantial regrowth and concomitantly increased expression of eptA and arnT were detected. Predominant l-Ara4N-modified lipid A species were detected in II-503Δmcr-1 following polymyxin B treatment.
conclusionsThis is the first study demonstrating a unique markerless deletion of mcr-1 in a clinical polymyxin-resistant K. pneumoniae. The current polymyxin B dosage regimens are suboptimal against K. pneumoniae, regardless of mcr, and can lead to the emergence of resistance.
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