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Synthesis, biological evaluation and membranotropic properties of quinoline-antimicrobial peptide conjugates as antibacterial drugs
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International audience. Tuberculosis and nosocomial infections are among the most frequent causes of death in the world. Mycobacteria such as Mycobacterium tuberculosis and ESKAPE bacteria are pathogens particularly implicated in these infectious diseases1. The lack of antibiotics with novel mode of action associated with the spread of drug resistant bacteria make the fight against these infections particularly challenging.Using antimicrobial peptides (AMPs) to restore or to broaden antibacterial activity of antibiotics is an interesting strategy to fight resistant strains. For example, the conjugation between chloramphenicol and ubiquicidine29-41 gives a conjugate with increased activity against Escherichia coli and reduced toxicity against neutrophils compared to chloramphenicol alone 2.During previous work on the development of new anti-infective drugs, we identified a series of quinolines active against Gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecalis. Concerning Gram-negative bacteria, some of them were active on E.coli but not against Pseudomonas aeruginosa3,4. In order to broaden the antibacterial spectrum of this heterocycle core, we synthesized quinoline-based conjugates with short AMP sequences5. Their antibacterial activities against a panel of bacteria and mycobacteria will be discussed. Membranotropic properties study through tensiometry measures on bacterial mimetic membrane models was carried out to elucidate their mechanism of action.
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