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In vitro reduction of colistin susceptibility and comparative genomics reveals multiple differences between MCR-positive and MCR-negative colistin-resistant Escherichia coli.

ABSTRACT: Objectives: Although resistance to colistin is increasingly reported from clinical settings, the genetic mechanisms that lead to colistin resistance in Escherichia coli have not been fully characterized. Here, we assess the evolution of colistin resistance in clinical isolates of mobilized colistin resistance (MCR)-negative and MCR-positive Escherichia coli. Methods: Spontaneously mutated colistin-resistant progeny were evolved using a step-wise reduction of colistin susceptibility. Resistance phenotypes were confirmed by minimum inhibitory concentration (MIC) determination, and the probable resistance mechanisms were investigated using PCR and reverse transcription-quantitative PCR. Mutated genes of the laboratory-evolved mutants were identified by whole-genome sequencing and comparative genomics. Fitness costs and serum resistance of the mutants were also compared to the corresponding wild types. Results: MCR-negative isolates displayed higher increases in MICs than did MCR-positive isolates following colistin exposure. Upregulation of pmrAB and associated genes was evident among MCR-negative isolates but not MCR-positive isolates. Comparative genomic analysis of mutants and their corresponding wild-types (WTs) revealed numerous mutations in genes encoding membrane transporters and two-component systems. Additionally, MCR-negative mutants exhibited higher fitness costs than MCR-positive mutants compared with their corresponding WTs but displayed similar serum resistance. Conclusion: Our findings reveal multiple differences between MCR-positive and MCR-negative E. coli strains following colistin exposure, which provide reference values for clinical medication.

SUBMITTER: Luo Q

PROVIDER: S-EPMC6580138 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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In vitro reduction of colistin susceptibility and comparative genomics reveals multiple differences between MCR-positive and MCR-negative colistin-resistant Escherichia coli.

Luo Qixia Q Niu Tianshui T Wang Yuan Y Yin Jianhua J Wan Fen F Yao Mingfei M Lu Haifeng H Xiao Yonghong Y Li Lanjuan L

Infection and drug resistance 20190612

Objectives: Although resistance to colistin is increasingly reported from clinical settings, the genetic mechanisms that lead to colistin resistance in Escherichia coli have not been fully characterized. Here, we assess the evolution of colistin resistance in clinical isolates of mobilized colistin resistance (MCR)-negative and MCR-positive Escherichia coli. Methods: Spontaneously mutated colistin-resistant progeny were evolved using a step-wise reduction of colistin ...[more]

PMID: 31354315

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Project description:Colistin is one of the last-resort antibiotics for infections caused by multidrug-resistant Gram-negative bacteria. However, the wide spread of novel plasmid-carrying colistin resistance genes mcr-1 and its variants substantially compromise colistin's therapeutic effectiveness and pose a severe danger to public health. To detect colistin-resistant microorganisms induced by mcr genes, rapid and reliable antibiotic susceptibility testing (AST) is imminently needed. In this study, we identified an RNA-based AST (RBAST) to discriminate between colistin-susceptible and mcr-1-mediated colistin-resistant bacteria. After short-time colistin treatment, RBAST can detect differentially expressed RNA biomarkers in bacteria. Those candidate mRNA biomarkers were successfully verified within colistin exposure temporal shifts, concentration shifts, and other mcr-1 variants. Furthermore, a group of clinical strains were effectively distinguished by using the RBAST approach during the 3-h test duration with over 93% accuracy. Taken together, our findings imply that certain mRNA transcripts produced in response to colistin treatment might be useful indicators for the development of fast AST for mcr-positive bacteria. IMPORTANCE The emergence and prevalence of mcr-1 and its variants in humans, animals, and the environment pose a global public health threat. There is a pressing urgency to develop rapid and accurate methods to identify MCR-positive colistin-resistant bacteria in the clinical samples, providing a basis for subsequent effective antibiotic treatment. Using the specific mRNA signatures, we develop an RNA-based antibiotic susceptibility testing (RBAST) for effectively distinguishing colistin-susceptible and mcr-1-mediated colistin-resistant strains. Meanwhile, the detection efficiency of these RNA biomarkers was evidenced in other mcr variants-carrying strains. By comparing with the traditional AST method, the RBAST method was verified to successfully characterize a set of clinical isolates during 3 h assay time with over 93% accuracy. Our study provides a feasible method for the rapid detection of colistin-resistant strains in clinical practice.

Dataset Information

In vitro reduction of colistin susceptibility and comparative genomics reveals multiple differences between MCR-positive and MCR-negative colistin-resistant Escherichia coli.

Publications

In vitro reduction of colistin susceptibility and comparative genomics reveals multiple differences between MCR-positive and MCR-negative colistin-resistant <i>Escherichia coli</i>.

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