Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 13, Pages 4466-4476Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.05.014
Keywords
Staphylococcus aureus; Bacillus anthracis; Helicase; High throughput screen; Aminocoumarin
Funding
- NIAID NIH HHS [R41 AI064974, U54 AI057159, R43 AI063712-01, R42 AI064974, AI064974, AI063712, R41 AI064974-02, R43 AI063712] Funding Source: Medline
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Antibacterial compounds with new mechanisms of action are needed for effective therapy against drug-resistant pathogens in the clinic and in biodefense. Screens for inhibitors of the essential replicative helicases of Bacillus anthracis and Staphylococcus aureus yielded 18 confirmed hits (IC50 <= 25 mu M). Several (5 of 18) of the inhibitors were also shown to inhibit DNA replication in permeabilized polA-deficient B. anthracis cells. One of the most potent inhibitors also displayed antibacterial activity (MIC similar to 5 mu g/ml against a range of Gram-positive species including bacilli and staphylococci) together with good selectivity for bacterial versus mammalian cells (CC50/MIC > 16) suitable for further optimization. This compound shares the bicyclic ring of the clinically proven aminocoumarin scaffold, but is not a gyrase inhibitor. It exhibits a mixed mode of helicase inhibition including a component of competitive inhibition with the DNA substrate (K-i = 8 mu M) and is rapidly bactericidal at 4 x MIC. (C) 2009 Elsevier Ltd. All rights reserved.
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