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

Antimicrobial Agents and Chemotherapy
Steven D PodosMichael J Pucci

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. There were no observable effects on growth rate in these mutants. Of 22 sequenced clones, 3 encoded point substitutions within the catalytic adenylation domain and 19 in the downstream oligonucleotide-binding (OB) fold and helix-hairpin-helix (HhH) domains. In vitro characterization of the enzymatic properties of four selected mutants revealed distinct signatures underlying their resistance to inhibition. The infrequent adenylation domain mutati...Continue Reading

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Citations

May 14, 2014·Analytical and Bioanalytical Chemistry·Eva StejskalováMiroslav Fojta
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Sep 16, 2021·Microbiology and Molecular Biology Reviews : MMBR·Kam Pou Ha, Andrew M Edwards

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