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Mutations in pmrB Confer Cross-Resistance between the LptD Inhibitor POL7080 and Colistin in Pseudomonas aeruginosa

Year: 2019
Type: article
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.
DOI: 10.1128/aac.00511-19
Authors: Keith P Romano, Thulasi Warrier, Bradley E Poulsen, Phuong H Nguyen, Alexander R Loftis, Azin Saebi, Bradley L Pentelute, Deborah T Hung
Institutions: Broad Institute, Brigham and Women's Hospital, Massachusetts General Hospital, Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard University, Massachusetts Institute of Technology
Language: English
Open Access status: hybrid
OpenAlex ID: W2952655373
FWCI: 1.641
Cites: 34
Cited by: 37
Related to: 10