No abstract

Methionine aminopeptidase (MetAP) is a promising target to develop novel antibiotics, because all bacteria express MetAP from a single gene that carries out the essential function of removing Nterminal methionine from nascent proteins. Divalent metal ions play a critical role in the catalysis, and there is an urgent need to define the actual metal used by MetAP in bacterial cells. By high throughput screening, we identified a novel class of catechol-containing MetAP inhibitors that display selectivity for the Fe(II)-form of MetAP. X-ray structure revealed that the inhibitor binds to MetAP at the active site with the catechol coordinating to the metal ions. Importantly, some of the inhibitors showed antibacterial activity at low micromolar concentration on Gram-positive and Gram-negative bacteria. Our data indicate that Fe(II) is the likely metal used by MetAP in the cellular environment, and MetAP inhibitors need to inhibit this metalloform of MetAP effectively to be therapeutically useful.

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.