Abstract
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.
Highlights
MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin
To determine whether mcr-1 affects bacterial growth rate and fitness, we examined growth curves, quantitative real-time PCR and competition assays for E. coli TOP10 carrying the mcr-1-pBAD plasmid construct
We explored whether MCR-1positive E. coli (MCRPEC) could generate high-level colistin resistance mutants (HLCRMs) over nonMCRPECs and investigated how damaging these changes would be
Summary
MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. 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. Whether the expression of mcr-1 gene modulates pathogenicity in E. coli remains to be explored Those few studies that have examined the association of MCRPEC with virulent factors and pathogenicity have shown little or no difference[16]. Colistin MICs displayed by MCRPEC are moderate (usually 2–8 mg l−1) when compared to the level of colistin resistance (usually 8–256 mg l−1) mediated by, for example, increased expression of pmrA/pmrB, inferring that the expression of mcr-1 is tightly controlled[3,9,10,16]. We analyse the viability, virulence and high-level colistin resistance stability of MCRPEC high-level colistin-resistant mutants
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