Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity

There is an urgent
need for new tuberculosis (TB) treatments, with
novel modes of action, to reduce the incidence/mortality of TB and
to combat resistance to current treatments. Through both chemical
and genetic methodologies, polyketide synthase 13 (Pks13) has been
validated as essential for mycobacterial survival and as an attractive
target for Mycobacterium tuberculosis growth inhibitors.
A benzofuran series of inhibitors that targeted the Pks13 thioesterase
domain, failed to progress to preclinical development due to concerns
over cardiotoxicity. Herein, we report the identification of a novel
oxadiazole series of Pks13 inhibitors, derived from a high-throughput
screening hit and structure-guided optimization. This new series binds
in the Pks13 thioesterase domain, with a distinct binding mode compared
to the benzofuran series. Through iterative rounds of design, assisted
by structural information, lead compounds were identified with improved
antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.