DOI: 10.1101/479618Nov 27, 2018Paper

Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane

BioRxiv : the Preprint Server for Biology
Akshay SabnisAndrew M Edwards

Abstract

Colistin is an antibiotic of last resort for infections caused by drug-resistant Gram-negative pathogens such as Pseudomonas aeruginosa and Escherichia coli. For this reason, high rates of treatment failure and resistance to this antibiotic are very concerning, and attempts to resolve these issues are hampered by a poor understanding of colistins mode of action. Whilst it is well established that colistin binds to lipopolysaccharide in the bacterial outer membrane, it was unclear how this led to bacterial killing. Here, we show that colistin also targets lipopolysaccharide in the cytoplasmic membrane and that this interaction is essential for cytoplasmic membrane permeabilisation, colistin-induced cell lysis and the bactericidal activity of the antibiotic. We also found that MCR-1-mediated colistin resistance confers protection against the antibiotic via the presence of modified lipopolysaccharide within the cytoplasmic membrane, rather than the outer membrane. These findings reveal key details about the mechanism by which colistin kills bacteria, providing the foundations for the development of new approaches to enhance therapeutic outcomes.

Related Concepts

Antibiotics
Bacterial Infections
Plasma Membrane
Colistin
Drug Resistance
Escherichia coli
Gram-Negative Bacteria
Lipopolysaccharides
Lysis
Pseudomonas aeruginosa

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