title: In vivo antibacterial activity and pharmacological properties of the membrane-active glycopeptide antibiotic YV11455.
abstract: The membrane-active glycopeptide antibiotic YV11455 is a lipophilic cationic vancomycin analogue that demonstrates rapid and concentration-dependent killing of clinically relevant multidrug-resistant (MDR) Gram-positive bacteria in vitro. YV11455 was 2-fold and 54-270-fold more effective than vancomycin against clinical isolates of vancomycin-sensitive and vancomycin-resistant bacteria, respectively. In this study, the in vivo efficacy, pharmacodynamics, pharmacokinetics and acute toxicology of YV11455 were investigated. In vivo activity and pharmacodynamics were determined in the neutropenic mouse thigh infection model against meticillin-resistant Staphylococcus aureus (MRSA). YV11455 produced dose-dependent reductions in MRSA titres in thigh muscle. When administered intravenously, the 50% effective dose (ED(50)) for YV11455 against MRSA was found to be 3.3 mg/kg body weight, and titres were reduced by up to ca. 3log(10)CFU/g from pre-treatment values at a dosage of 12 mg/kg with single treatment. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged half-life, with an increase in drug exposure (area under the concentration-time curve) compared with vancomycin. The peak plasma concentration following an intravenous dose of 12 mg/kg was 543.5 μg/mL. Acute toxicology studies revealed that YV11455 did not cause any significant alterations in biochemical parameters or histological pictures related to major organs such as the liver and kidney at its pharmacodynamic endpoint (ED(3-log kill)). These findings collectively suggest that YV11455 could be used clinically for the treatment of infections caused by MDR Gram-positive bacteria.
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 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, Jakkur, Bangalore 560064, Karnataka, India.
authors.forename: Mohini M
authors.initials: MM
authors.lastname: Konai
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, Karnataka, India.
authors.forename: Goutham B
authors.initials: GB
authors.lastname: Manjunath
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, Karnataka, India.
authors.forename: Relekar G
authors.initials: RG
authors.lastname: Prakash
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bangalore 560024, Karnataka, India.
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Mani
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bangalore 560024, Karnataka, India.
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Paramanandham
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bangalore 560024, Karnataka, India.
authors.forename: Shome B
authors.initials: SB
authors.lastname: Ranjan
authors.affiliation: Department of Neuromicrobiology, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560029, Karnataka, India.
authors.forename: Raju
authors.initials: R
authors.lastname: Ravikumar
authors.affiliation: Immunology and Microbiology Laboratory, Department of Human Physiology with Community Health, Vidyasagar University, Midnapore 721102, West Bengal, India.
authors.forename: Subhankari P
authors.initials: SP
authors.lastname: Chakraborty
authors.affiliation: Immunology and Microbiology Laboratory, Department of Human Physiology with Community Health, Vidyasagar University, Midnapore 721102, West Bengal, India.
authors.forename: Somenath
authors.initials: S
authors.lastname: Roy
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, Karnataka, India. Electronic address: jayanta@jncasr.ac.in.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D058491:Bacterial Load; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006020:Glycopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007677:Kidney Function Tests; D008111:Liver Function Tests; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D009132:Muscles / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D014640:Vancomycin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D014640:Vancomycin
keywords: Antibiotic resistance; Glycopeptide antibiotics; In vivo efficacy; Membrane-active antibiotic; Pharmacological properties; Vancomycin-resistant bacteria