Circumventing colistin resistance by combining colistin and antimicrobial peptides to kill colistin-resistant and multidrug-resistant Gram-negative bacteria.

Journal of Global Antimicrobial Resistance
Kaitlin S WitherellDouglas R Call

Abstract

Colistin is a 'last-line' antibiotic used to treat multidrug-resistant Gram-negative bacteria, but colistin resistance has emerged. Colistin normally binds to the lipid A moiety on the bacterial outer membrane, where it then destroys the bacterial membrane. Mobilize colistin resistance (MCR, encoded by mcr-1 and others) is a phosphoethanolamine transferase that modifies lipid A, preventing colistin binding. We hypothesized that combining pore-forming AMPs and colistin will circumvent this mechanism and reduce the minimum inhibitory concentration (MIC) of colistin for both colistin- and multidrug-resistant Gram-negative bacteria. In vitro cultures were incubated for 18 h after combining bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa) with serially diluted colistin and a fixed concentration of peptide MSI-78 or OTD-244. When combined with either peptide, the colistin MIC decreased more than 4-fold for 88% of all tested isolates (n = 17; range, 4-64-fold reduction) and for 75% of colistin-resistant isolates (n = 8; range, 4-64-fold reduction). The concentrations used had no effect on red blood cells based on a conventional haemolysis assay. These findings are consistent with t...Continue Reading

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