title: In vivo efficacy and pharmacological properties of a novel glycopeptide (YV4465) against vancomycin-intermediate Staphylococcus aureus.
abstract: Infections caused by vancomycin-intermediate Staphylococcus aureus (VISA) are associated with high rates of vancomycin treatment failure. The lipophilic vancomycin-carbohydrate conjugate YV4465 is a new glycopeptide antibiotic that is active against a variety of clinically relevant multidrug-resistant Gram-positive pathogens in vitro. YV4465 was 50- and 1000-fold more effective than vancomycin against VISA and vancomycin-resistant enterococci, respectively. This study evaluated the in vivo efficacy against VISA as well as the pharmacokinetics and toxicology of YV4465. A neutropenic mouse thigh infection model was used for the determination of efficacy and pharmacodynamic properties against VISA. YV4465 produced a dose-dependent reduction in VISA titres in thigh muscle; bacterial titres were reduced by up to ca. 2log(10)CFU/g from the pre-treatment titre at a dosage of 8 mg/kg. Single-dose pharmacokinetic studies demonstrated an increase in drug exposure to the animal following linear kinetics with a prolonged half-life (t(1/2)) compared with vancomycin. The peak plasma concentration (C(max)) following an intravenous dose of 12 mg/kg was 703 μg/mL. Acute toxicology studies revealed that YV4465 did not cause any significant alterations in biochemical parameters related to major organs such as the liver and kidneys at its pharmacodynamic endpoint (>ED(2-log kill)). These studies demonstrate that YV4465 has the potential to be developed as a next-generation glycopeptide antibiotic for the treatment of infections caused by VISA.
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, India.
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Yarlagadda
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, India.
authors.forename: Mohini M
authors.initials: MM
authors.lastname: Konai
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bengaluru 560024, Karnataka, India.
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Paramanandham
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bengaluru 560024, Karnataka, India.
authors.forename: Venugopal C
authors.initials: VC
authors.lastname: Nimita
authors.affiliation: National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Hebbal, Bengaluru 560024, Karnataka, India.
authors.forename: Bibek R
authors.initials: BR
authors.lastname: Shome
authors.affiliation: Chemical Biology & Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, India. Electronic address: jayanta@jncasr.ac.in.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D058491:Bacterial Load; D004195:Disease Models, Animal; D005260:Female; D006020:Glycopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051379:Mice; D010949:Plasma / Q000737:chemistry; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013848:Thigh / Q000382:microbiology; D016896:Treatment Outcome; D020713:Vancomycin Resistance
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides
keywords: Antibiotic resistance; Glycopeptide antibiotics; In vivo antibacterial activity; Vancomycin; Vancomycin-resistant bacteria