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Volume 167, Issue 11

Colistin resistance in confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic Open Access

Abstract

Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug-resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to bacterial death and lysis. Colistin resistance in occurs via mutations in the chromosome or the acquisition of mobilized colistin-resistance () genes. Both these colistin-resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other genes, or resistance due to chromosomal mutations. Using a panel of clinical that had acquired −1, –1.5, −2, –3, −3.2 or −5, or had acquired polymyxin resistance independently of genes, we found that almost all isolates were susceptible to colistin-mediated permeabilization of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilization of the outer membrane of colistin-resistant isolates by the polymyxin is in turn sufficient to sensitize bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in these isolates is due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance.

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  • Accepted:
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Keyword(s): colistin , E. coli , lipopolysaccharide , MCR , polymyxin and resistance
Funding
This study was supported by the:
  • National Institute for Health Research (Award Imperial Biomedical Research Centre)
    • Principle Award Recipient: AndrewM Edwards
  • Wellcome Trust (Award 105603/Z/14/Z)
    • Principle Award Recipient: GeraldJ Larrouy-Maumus
  • Wenner-Gren Stiftelserna (Award UPD2019-0174)
    • Principle Award Recipient: ChristopherD Furniss
  • Medical Research Council (Award MR/M009505/1)
    • Principle Award Recipient: DespoinaA. I. Mavridou
  • Medical Research Council (Award MR/N014103/1)
    • Principle Award Recipient: AkshaySabnis
© 2021 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2021-11-01
2024-04-19
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Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic
Microbiology 167, 001104 (2021); https://doi.org/10.1099/mic.0.001104
/content/journal/micro/10.1099/mic.0.001104
/content/journal/micro/10.1099/mic.0.001104
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