Membrane active vancomycin analogues: a strategy to combat bacterial resistance.
The alarming growth of antibiotic resistant superbugs such as vancomycin-resistant Enterococci and Staphylococci has become a major global health hazard. To address this issue, we report the development of lipophilic cationic vancomycin analogues possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compounds were shown to be bactericidal at low concentrations and did not induce bacterial resistance. An optimized compound in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no observed toxicity. The remarkable activity of these compounds is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics.
Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka India.
Venkateswarlu
V
Yarlagadda
Padma
P
Akkapeddi
Goutham B
GB
Manjunath
Jayanta
J
Haldar
D000818:Animals; D016470:Bacteremia / Q000188:drug therapy; D002463:Cell Membrane Permeability; D024881:Drug Resistance, Bacterial; D016983:Enterococcus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006461:Hemolysis; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000150:complications / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D000644:Quaternary Ammonium Compounds; D014230:Triazoles; D014640:Vancomycin