Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-017-02149-0
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Funding
- MRC grant DETER-XDR-CHINA [MR/P007295/1]
- CSC Scholarship
- Geneva University Hospitals (HUG)
- Swiss National Science Foundation [P300PB_171601]
- Royal Golden Jubilee-PhD Program from Thailand Research Fund
- Rajamangala University of Technology Lanna [PHD/0054/2555]
- Swiss National Science Foundation (SNF) [P300PB_171601] Funding Source: Swiss National Science Foundation (SNF)
- Medical Research Council [MR/P007295/1, MR/N028317/1] Funding Source: researchfish
- MRC [MR/P007295/1, MR/N028317/1] Funding Source: UKRI
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MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. Here, we analyse the impact of MCR-1 expression on E. coli morphology, fitness, competitiveness, immune stimulation and virulence. Increased expression of mcr-1 results in decreased growth rate, cell viability, competitive ability and significant degradation in cell membrane and cytoplasmic structures, compared to expression of catalytically inactive MCR-1 (E246A) or MCR-1 soluble component. Lipopolysaccharide (LPS) extracted from mcr-1 strains induces lower production of IL-6 and TNF, when compared to control LPS. Compared to their parent strains, high-level colistin resistance mutants (HLCRMs) show reduced fitness (relative fitness is 0.41-0.78) and highly attenuated virulence in a Galleria mellonella infection model. Furthermore, HLCRMs are more susceptible to most antibiotics than their respective parent strains. Our results show that the bacterium is challenged to find a delicate equilibrium between expression of MCR-1-mediated colistin resistance and minimalizing toxicity and thus ensuring cell survival.
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