Outer-membrane-acting peptides and lipid II-targeting antibiotics cooperatively kill Gram-negative pathogens
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Li, Q., Cebrián, R., Montalbán-López, M., Ren, H., Wu, W., & Kuipers, O. P. (2021). Outer-membrane-acting peptides and lipid II-targeting antibiotics cooperatively kill Gram-negative pathogens. Communications Biology, 4(1), 1-11. [DOI: 10.1038/s42003-020-01511-1]
SponsorshipChina Scholarship Council 201306770012; European Union (EU); NWO-NACTAR program
The development and dissemination of antibiotic-resistant bacterial pathogens is a growing global threat to public health. Novel compounds and/or therapeutic strategies are required to face the challenge posed, in particular, by Gram-negative bacteria. Here we assess the combined effect of potent cell-wall synthesis inhibitors with either natural or synthetic peptides that can act on the outer-membrane. Thus, several linear peptides, either alone or combined with vancomycin or nisin, were tested against selected Gram-negative pathogens, and the best one was improved by further engineering. Finally, peptide D-11 and vancomycin displayed a potent antimicrobial activity at low μM concentrations against a panel of relevant Gram-negative pathogens. This combination was highly active in biological fluids like blood, but was non-hemolytic and non-toxic against cell lines. We conclude that vancomycin and D- 11 are safe at >50-fold their MICs. Based on the results obtained, and as a proof of concept for the newly observed synergy, a Pseudomonas aeruginosa mouse infection model experiment was also performed, showing a 4 log10 reduction of the pathogen after treatment with the combination. This approach offers a potent alternative strategy to fight (drug-resistant) Gram-negative pathogens in humans and mammals.