title: Antimicrobial evaluation of nocathiacins, a thiazole peptide class of antibiotics.
abstract: Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-positive bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compounds against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain additional structurally related compounds. The MIC assay results of BMS-249524 and two more water-soluble derivatives, BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-positive pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Analysis of killing kinetics revealed that these compounds are bactericidal for S. aureus with at least a 3-log(10) reduction of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compounds demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-positive bacterial pathogens.
authors.affiliation: Achillion Pharmaceuticals, 300 George St., New Haven, CT 06511, USA. mpucci@achillion.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pucci
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: John F
authors.initials: JF
authors.lastname: Barrett
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: DenBleyker
authors.forename: Linda F
authors.initials: LF
authors.lastname: Discotto
authors.forename: Joan C
authors.initials: JC
authors.lastname: Fung-Tomc
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Ueda
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics; D001421:Bacteria, Anaerobic / Q000187:drug effects; D004252:DNA Mutational Analysis; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009161:Mycobacterium / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D013844:Thiazoles; D014640:Vancomycin