Aryloxyphenol PA74 potentiates polymyxin B against multidrug-resistant Gram-negative bacteria and improves murine infection outcomes.

The escalating crisis of antimicrobial resistance (AMR), particularly in Gram-negative pathogens like Acinetobacter baumannii, necessitates urgent therapeutic innovation. Current last-resort antibiotics, such as polymyxins, face increasing resistance and significant toxicity concerns, limiting their clinical utility. Adjuvant compounds that restore or enhance existing antibiotic efficacy offer a promising strategy to circumvent resistance mechanisms and extend the lifespan of critical antimicrobials, addressing a key gap in drug development.

Researchers employed high-throughput screening to identify PA74, an aryloxyphenol, as a potential polymyxin adjuvant. They conducted checkerboard analyses to assess synergy against polymyxin-resistant strains of A. baumannii, K. pneumoniae, and E. coli. Serial passage assays compared resistance development between PA74 and triclosan. Cytotoxicity assays evaluated PA74's safety profile across mammalian cell lines. Functional analyses using FabI-overexpressing and point-mutant bacterial strains probed PA74's mechanism. In vivo efficacy was tested in a murine skin infection model, comparing polymyxin B alone versus co-treatment with PA74.

PA74 demonstrated significant potentiation of polymyxin B activity against polymyxin-resistant Acinetobacter baumannii, as well as Klebsiella pneumoniae and Escherichia coli. Beyond polymyxins, PA74 also enhanced the activity of tetracycline and chloramphenicol, suggesting broader utility. Structurally similar to triclosan, PA74 exhibited a markedly lower propensity for resistance development over 15 days of serial passage. Importantly, PA74 showed minimal cytotoxicity across various mammalian cell lines, indicating a favorable safety profile. Functional studies revealed that increased FabI abundance attenuated the synergistic effect of the polymyxin B-PA74 combination, strongly implicating FabI in PA74's mechanism of action. > PA74 co-treatment significantly improved therapeutic outcomes in a murine skin infection model, establishing its in vivo efficacy as a polymyxin B adjuvant.