Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics.

Abstract:

:Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram-negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram-positive bacteria poses a viable therapeutic alternative for highly drug-resistant Gram-negative pathogens expressing mcr-1.

journal_name

Nat Commun

journal_title

Nature communications

authors

MacNair CR,Stokes JM,Carfrae LA,Fiebig-Comyn AA,Coombes BK,Mulvey MR,Brown ED

doi

10.1038/s41467-018-02875-z

subject

Has Abstract

pub_date

2018-01-31 00:00:00

pages

458

issue

1

issn

2041-1723

pii

10.1038/s41467-018-02875-z

journal_volume

9

pub_type

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