title: A Vancomycin Derivative with a Pyrophosphate-Binding Group: A Strategy to Combat Vancomycin-Resistant Bacteria.
abstract: Vancomycin, the drug of last resort for Gram-positive bacterial infections, has also been rendered ineffective by the emergence of resistance in such bacteria. To combat the threat of vancomycin-resistant bacteria (VRB), we report the development of a dipicolyl-vancomycin conjugate (Dipi-van), which leads to enhanced inhibition of cell-wall biosynthesis in VRB and displays in vitro activity that is more than two orders of magnitude higher than that of vancomycin. Conjugation of the dipicolyl moiety, which is a zinc-binding ligand, endowed the parent drug with the ability to bind to pyrophosphate groups of cell-wall lipids while maintaining the inherent binding affinity for pentapeptide termini of cell-wall precursors. Furthermore, no detectable resistance was observed after several serial passages, and the compound reduced the bacterial burden by a factor of 5 logs at 12 mg kg(-1) in a murine model of VRB kidney infection. The findings presented in this report stress the potential of our strategy to combat VRB 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: Paramita
authors.initials: P
authors.lastname: Sarkar
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: 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 / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D003959:Diamines / Q000737:chemistry; D011756:Diphosphates / Q000737:chemistry*; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000382:microbiology / Q000662:veterinary; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020713:Vancomycin Resistance / Q000187:drug effects; D015032:Zinc / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D003959:Diamines; D011756:Diphosphates; D014640:Vancomycin; D015032:Zinc; C007297:1,6-diaminohexane
keywords: antibiotics; bacterial resistance; drug design; multidrug-resistant bacteria; vancomycin