Tuberculosis (TB) is a major global health problem causing approximately 1.8 million deaths worldwide each year. Currently available first-line TB drugs are becoming less effective due to the development of resistance in Mycobacterium tuberculosis (Mtb), the causative agent of TB. Additionally, the second-line drugs used in the drug-resistant TB treatment have side effects, further underscoring an urgent need for new and safer alternatives for curing drug-resistant TB. We have recently published the structure-based development of a novel benzofuran based lead which kills Mtb by targeting the polyketide synthase 13 (Pks13), an essential enzyme involved in the biosynthesis of mycolic acids which are crucial components of the mycobacterial cell wall. Our investigation led to the identification and validation of the thioesterase domain of Pks13 (Pks13 TE) as a new drug target in Mtb. X-ray crystal structure of Pks13 TE domain in complex with the original hit molecule was used to guide medicinal chemistry for the development of our lead, TAM16. Subsequently, crystal structure of Pks13 TE-TAM16 complex were used to develop an alternative series of inhibitors. A small focus library of doubly homologated benzofuran derivatives was synthesized and their structure-activity relationships against Pks13 TE domain were tracked using biochemical and whole-cell based assays. Compounds exhibiting good potency were further subjected to safety and pharmacokinetic profiling. These new series of RCD compounds with potent bactericidal activity against Mtb developed recently in our laboratory will be discussed in the presentation.

Synthesis and optimization of novel inhibitors targeting M. tuberculosis polyketide synthase 13 thioesterase domain

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.