RESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Péptidos Cíclicos/farmacología , Tiazoles/farmacología , Bacterias/genética , Bacterias Anaerobias/efectos de los fármacos , Análisis Mutacional de ADN , Cinética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Mycobacterium/efectos de los fármacos , Vancomicina/farmacologíaRESUMEN
A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.
Asunto(s)
Antibacterianos/síntesis química , Isoxazoles/química , Nitrógeno/química , Oxazolidinonas/química , Oxazolona/análogos & derivados , Oxazolona/química , Antibacterianos/química , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Oxazolona/síntesis química , Oxazolona/farmacología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of imidazolinone analogues was synthesized and shown to possess potent MurB inhibitory as well as good antibacterial activity.