Mechanistic assessment of DNA ligase as an antibacterial target in Staphylococcus aureus.

ABSTRACT: We report the use of a known pyridochromanone inhibitor with antibacterial activity to assess the validity of NAD(+)-dependent DNA ligase (LigA) as an antibacterial target in Staphylococcus aureus. Potent inhibition of purified LigA was demonstrated in a DNA ligation assay (inhibition constant [K(i)] = 4.0 nM) and in a DNA-independent enzyme adenylation assay using full-length LigA (50% inhibitory concentration [IC(50)] = 28 nM) or its isolated adenylation domain (IC(50) = 36 nM). Antistaphylococcal activity was confirmed against methicillin-susceptible and -resistant S. aureus (MSSA and MRSA) strains (MIC = 1.0 μg/ml). Analysis of spontaneous resistance potential revealed a high frequency of emergence (4 × 10(-7)) of high-level resistant mutants (MIC > 64) with associated ligA lesions. Th

SUBMITTER: Podos SD 

PROVIDER: S-EPMC3421614 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature