This week in TB R&D – 10 August 2010

10 Aug 2010
by Working Group

2.1 Å DNA gyrase complex with GSK299423 (Figure 2 from paper)

This week we reposted an article from regarding a new antibactierial compound from GlaxoSmithKline (GSK). GSK has recently published a Nature paper describing the 2.1 angstom crystal structure of Staphylococcus aureus DNA gyrase (a Type IIA topoisomerase) and DNA in complex with their new broad-spectrum antibacterial compound (GSK299423).

GSK299423 is a novel bacterial topoisomerase inhibitor (NBTI) that is not a fluoroquinolone. According to the authors, GSK299423 was optimized from a chemical series identified from an unbiased antibacterial screen (referenced a 1999 European patent by Coates et al entitled ‘Preparation of Piperidinylalklquinolines as Antibacterials).

Results from the crystal structure reveal that the mechanism of inhibition of this compound is distinct from fluoroquinolones by apparently stabilizing the enzyme-DNA comples in a pre-cleavage conformation. Furthermore, GSK299423 binds to a region that does not overlap with the two known quinolone binding sites. Supplementary results suggested that GSK299423 is active and very potent against various Gram-positive and Gram-negative bacterial strains, including fluoroquinolone resistant strains, although M. tb was not directly examined.

These are important findings considering the need for new TB drugs and the prevalence and growing rate of quinolone resistant in bacterical strains including TB.

Should this compound be considered in the CPTR initiative to identify novel TB drug regimens? What potential liabilities if any can be predicted since the binding site of this compound is near to the quinolone binding sites? What are your additional questions and thoughts? Please share them below.

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