uridine-diphosphate-n-acetylmuramic-acid and Gram-Negative-Bacterial-Infections

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 log

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Microbial Sensitivity Tests; Nisin; Peptides; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin