RT Journal Article
T1 Outer-membrane-acting peptides and lipid II-targeting antibiotics cooperatively kill Gram-negative pathogens.
A1 Li, Qian
A1 Cebrián, Rubén
A1 Montalbán-López, Manuel
A1 Ren, Huan
A1 Wu, Weihui
A1 Kuipers, Oscar P
AB 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.
YR 2021
FD 2021-01-04
LK http://hdl.handle.net/10668/16918
UL http://hdl.handle.net/10668/16918
LA en
DS RISalud
RD Apr 5, 2025