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Background and objectives:
Cationic surfactants are potent antimicrobials and include benzalkonium chloride (BAC), a common disinfectant, and pexiganan (PEX), a therapeutic antimicrobial peptide. Both BACs and PEX act on bacterial membranes. But do these similarities lead to the similarities in resistance mechanisms and cross-resistance, compromising their clinical use?
Materials and methods:
Stable resistant mutants of Staphylococcus aureus were generated by passaging daily in increasing concentrations of BAC or PEX, and analysed by whole genome sequencing and metabolomics. Minimum inhibitory concentrations were determined for BAC, PEX and a panel of antibiotics. Fitness costs were assessed by growth curves.
Results:
Adaptation to PEX was fast and high-level (32-fold, five transfers) compared to BAC (4-fold, seven transfers). Mutations associated with phospholipid metabolism and efflux pump activity were found in PEX and BAC mutants, respectively. Metabolomics confirmed vastly different cellular responses. There were no changes in cross-resistance to BAC, PEX and antibiotics. PEX mutants had high fitness costs, while BAC mutants showed none.
Conclusion:
We find no support that concurrent use of PEX and BAC results in mutual cross-resistance and resistance to antibiotics in S. aureus due to a shared mechanism of action. While low level of resistance evolution recommends BACas an efficient biocide against Staphylococci, absence of fitness costs in resistant mutants is worrying.