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

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.