Thiolactomycin-based β-ketoacyl-AcpM synthase a (KasA) inhibitors: Fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy

Thiolactomycin (TLM) is a natural product inhibitor of KasA, the β-ketoacyl synthaseAfrom Mycobacterium tuberculosis. To improve the affinity of TLM for KasA, a series of TLM analogs have been synthesized based on interligand NOEs betweenTLM and a pantetheine analog when both are bound simultaneously to the enzyme. Kinetic binding data reveal that position 3 of the thiolactone ring is a suitable position for elaboration of theTLM scaffold, and the structure-activity relationship studies provide information on the molecular features that govern time-dependent inhibition in this enzyme system. These experiments also exemplify the utility of transient one-dimensional NOE spectroscopy for obtaining interligand NOEs compared with traditional steady state two-dimensional NOESY spectroscopy.