Mutations in pmrB Confer Cross-Resistance between the LptD Inhibitor POL7080 and Colistin in Pseudomonas aeruginosa
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Mutations in pmrB Confer Cross-Resistance between the LptD Inhibitor POL7080 and Colistin in Pseudomonas aeruginosa

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

DOI: 10.1128/AAC.00511-19


Keith P. Romano, Thulasi Warrier, Bradley E. Poulsen, Phuong H. Nguyen, Alexander R. Loftis, Azin Saebi, Bradley L. Pentelute, Deborah T. Hung

Abstract

Pseudomonas aeruginosa is a major bacterial pathogen associated with a rising prevalence of antibiotic resistance. We evaluated the resistance mechanisms of P. aeruginosa against POL7080, a species-specific, first-in-class antibiotic in clinical trials that targets the lipopolysaccharide transport protein LptD. We isolated a series of POL7080-resistant strains with mutations in the two-component sensor gene pmrB. Transcriptomic and confocal microscopy studies support a resistance mechanism shared with colistin, involving lipopolysaccharide modifications that mitigate antibiotic cell surface binding.

Category
2019, Publications