NBTI's (novel bacterial topoisomerase inhibitors) are a new class of gyrase and topoisomerase IV inhibitors which act by a different mechanism to fluoroquinolones, and avoid target mediated cross-resistance. Since GSKs original disclosure of this novel antibiotic class, multiple companies have now reported discovery efforts.Lead optimization in the NBTI class had to address antibacterial potency and spectrum in addition to multiple toxicity issues including hERG inhibition, genetic toxicology and species specific retinal pigment epithelium effects.GSK solved the first X-ray structure of a NBTI inhibitor in complex with S.aureusDNA gyrase and DNA providing unprecedented knowledge for lead optimization and the design of novel inhibitors.Optimization of the Gram positive selective early leads led to new series which afforded good activity versus some Gram negative pathogens and identification of development candidates from the NBTI class encompassing pathogens implicated in hCAP and SSTI. Two NBTIs were progressed to early Phase I studies and GSK2140944 was selected as the optimal molecule for continued progression.GSK2140944 has good activity versus a range of biothreat pathogens and exploitation of this molecule was part-supported by the US DoD Defense Threat Reduction Agency (DTRA). GSK2140944 is being evaluated for use versus both biothreat and conventional pathogens.Acknowledgements This work was part supported by the Transformational Medical Technologies Program (HDTRA1-07-9-0002) from the Department of Defense, Joint Chemical and Biological Defense Program through the Defense Threat Reduction Agency (DTRA). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Department of Defense or the US Government.

Exploiting novel bacterial topoisomerase inhibitors (NBTIs) as a new class of antibiotic

246th National Meeting (2013)

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