title: Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models.
abstract: NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development. After intravenous dosing NVB333 has high exposure in mouse plasma and shows generally improved in vivo activity compared with vancomycin in mouse infection models despite modest MIC values. In thigh infection models, promising efficacy was demonstrated against several strains of S. aureus including methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) strains, and against Enterococcus faecalis UNT126-3. Area under the concentration curve (AUC)/MIC was shown to be the best predictor of efficacy against S. aureus UNT103-3 with an AUC/MIC of 138 (uncorrected for protein binding) achieving a static effect. NVB333 was also effective in a disseminated infection model where it conferred complete survival from the MRSA strain ATCC 33591. NVB333 showed rather modest lung penetration after intravenous dosing (AUC in lung 2-3% of plasma AUC), but because of very high plasma exposure, therapeutic levels of compound were achieved in the lung. Efficacy at least equal to vancomycin was demonstrated against an MRSA strain (UNT084-3) in a bronchoalveolar infection model. The impressive in vivo efficacy of NVB333 and strong resistance prognosis makes this compound an interesting candidate for development for treating systemic Gram-positive infections.
authors.affiliation: Novacta Biosystems and Cantab Anti-infectives, BioPark, Welwyn Garden City, Hertfordshire, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Boakes
authors.affiliation: University of North Texas Health Science Center, Fort Worth, TX, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.affiliation: Novacta Biosystems and Cantab Anti-infectives, BioPark, Welwyn Garden City, Hertfordshire, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Vinson
authors.affiliation: Novacta Biosystems and Cantab Anti-infectives, BioPark, Welwyn Garden City, Hertfordshire, UK.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Wadman
authors.affiliation: Novacta Biosystems and Cantab Anti-infectives, BioPark, Welwyn Garden City, Hertfordshire, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dawson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001430:Bacteriocins / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D017850:Economics, Pharmaceutical; D013293:Enterococcus faecalis / Q000187:drug effects; D005260:Female; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins