Inhibition of Mycobacterium tuberculosis methionine aminopeptidases by bengamide derivatives

Abstract

Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target to develop novel antitubercular agents. Natural bengamides potently inhibit proliferation of mammalian cells by targeting MetAP enzymes, and the X-ray structure of human type 2 MetAP in complex with a bengamide derivative revealed the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1a and MtMetAP1c in different metalloforms, inhibition of growth of M. tuberculosis in replicating and non-replicating states, and inhibition of growth of human K562 cells. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M. tuberculosis were observed for some of these derivatives. X-ray structures of MtMetAP1c in complex with two of the derivatives provided the valuable structural information for improvement of these inhibitors for potency and selectivity.