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

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.

Identification of Genes Required for Resistance to Peptidomimetic Antibiotics by Transposon Sequencing

“…However, even the relatively small differences in susceptibility were sufficient to allow selection of mutants in the LPS modification pathway in our Tn-Seq analysis, indicating the high sensitivity of the experimental approach. Our data also support the findings of a recent study, in which strains resistant to POL7080 were isolated and shown to carry a mutation in the pmrB gene (Romano et al, 2019).…”

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology

“…Concerningly, resistance to this compound may already exist and/or drive resistance to other antimicrobials. Romano et al reported that resistance (4 -32-fold change in MIC) to POL7080 can develop through pmrB mutations that upregulate the arn operon, resulting in decreased binding to the cell surface and the development of cross-resistance to colistin [193].…”

Understanding resistance in Pseudomonas

“…The arsenal of antibiotics against MDR/XDR P. aeruginosa is awaiting promising molecules (Supplementary Table 1) [5,[9][10][11]. Two molecules in late-stage of development are quite promising in the treatment of XDR P. aeruginosa, because they retain activity in the presence of metallo-enzymes; cefiderocol and cefepime-zidebactam due to their extended spectrum, encompassing all current mechanisms of resistance in MDR and XDR P. aeruginosa [5,9,10].…”