title: Membrane Disruption and Enhanced Inhibition of Cell-Wall Biosynthesis: A Synergistic Approach to Tackle Vancomycin-Resistant Bacteria.
abstract: Resistance to glycopeptide antibiotics, the drugs of choice for life-threatening bacterial infections, is on the rise. In order to counter the threat of glycopeptide-resistant bacteria, we report development of a new class of semi-synthetic glycopeptide antibiotics, which not only target the bacterial membrane but also display enhanced inhibition of cell-wall biosynthesis through increased binding affinity to their target peptides. The combined effect of these two mechanisms resulted in improved in vitro activity of two to three orders of magnitude over vancomycin and no propensity to trigger drug resistance in bacteria. In murine model of kidney infection, the optimized compound was able to bring bacterial burden down by about 6 logs at 12 mg kg(-1) with no observed toxicity. The results furnished in this report emphasize the potential of this class of compounds as future antibiotics for drug-resistant Gram-positive infections.
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka (India).
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Yarlagadda
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka (India).
authors.forename: Sandip
authors.initials: S
authors.lastname: Samaddar
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Yelahanka, Bengaluru 560064 (India).
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Paramanandham
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Yelahanka, Bengaluru 560064 (India).
authors.forename: Bibek R
authors.initials: BR
authors.lastname: Shome
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru 560064, Karnataka (India). jayanta@jncasr.ac.in.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000166:cytology / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D014640:Vancomycin
keywords: antibiotics; bacterial resistance; drugs design; multidrug-resistant bacteria; vancomycin