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bioRxiv · 10.1101/571224

Mutations in pmrB confer cross-resistance to the LptD inhibitor POL7080 and colistin in Pseudomonas aeruginosa

Romano, K. P.·Warrier, T.·Poulsen, B. E.·Nguyen, P. H.·Loftis, A. R.·Saebi, A.·Pentelute, B. L.·Hung, D. T.
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Abstract

Pseudomonas aeruginosa is a major bacterial pathogen for which there is rising antibiotic resistance. We evaluated the resistance mechanisms of P. aeruginosa against POL7080, a species-specific, first-in-class antibiotic in phase 3 clinical trials targeting the lipopolysaccharide transport protein LptD. We found resistance mutations in the two-component regulator pmrB. Genome-wide transcriptomics and confocal microscopy studies together suggest that POL7080 is vulnerable to the same resistance mechanisms described previously for polymyxins, including colistin, that involve lipid A modifications to mitigate antibiotic cell surface binding.

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Romano, K. P., Warrier, T., Poulsen, B. E., Nguyen, P. H., Loftis, A. R., Saebi, A., Pentelute, B. L., Hung, D. T.. 2019-03-08. Mutations in pmrB confer cross-resistance to the LptD inhibitor POL7080 and colistin in Pseudomonas aeruginosa. https://doi.org/10.1101/571224

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