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.

Advances in Bacterial Methionine Aminopeptidase Inhibition

“…In addition to the classes of bacterial MetAP inhibitors discussed, other classes of inhibitors have been identified, such as barbiturates [66], salicylate derivatives [33,67], catechols [43,64,65,68] and bengamide derivatives [69]. In general, the barbiturate based inhibitors exhibit moderate activity against Ec MetAP1 (K i = 4 – 517 μM, Co(II) cofactors) [66], with only one compound exhibiting potent activity (K i = 0.05 μM) and were found to be nonselective inhibitors of MetAPs, as demonstrated by comparable activity with Hs MetAP1.…”

“…Finally, bengamide derivatives have demonstrated activity against Mt MetAP1a and Mt MetAP1c and have been crystallized with Mt MetAP1 (PDB: 3PKC, 3PKD, 3PKE) [69,70]. The general structure of these inhibitors is shown below and the compounds chelate both active site metals via the 1,2,3-triol chain.…”

“…Although these compounds exhibit potent activity against MetAP in enzymatic assays (( 64 ): Mt MetAP1c IC 50 = 39, 0.40, 150 and 61 μM; Co(II), Mn(II), Ni(II) and Fe(II) cofactors, respectively), they do not exhibit large differences in activity for the various substitution patterns, as demonstrated by the differences in activity for compounds ( 64 ) and ( 65 ) ( Mt MetAP1c IC 50 = 52, 0.2, >250 and 68 μM; Co(II), Mn(II), Ni(II) and Fe(II) cofactors, respectively) [69]. Additionally, they are essentially inactive against M. tuberculosis in a microplate Alamar Blue (MABA) cellular growth inhibition assay (( 64 ) % inhibition at 128 μM = 15%; ( 65 ) % inhibition at 128 μM = 48%) [69].…”

“…Additionally, they are essentially inactive against M. tuberculosis in a microplate Alamar Blue (MABA) cellular growth inhibition assay (( 64 ) % inhibition at 128 μM = 15%; ( 65 ) % inhibition at 128 μM = 48%) [69]. Therefore, more research must be conducted to maximize activity if these compounds are to progress from hit identification to lead refinement.…”

Produktion mariner Naturstoffe aus der Klasse der Bengamide in Myxobakterien: Biosynthese und Struktur‐Aktivitäts‐Beziehungen

“…BenI in M. virescens ST20011 stellt eine zusätzliche Kopie von MetAP1b dar,w as in Anbetracht der Wirkweise der Bengamide als MetAP-Inhibitoren [10] . [12] ii)Humane MetAP (PDB:1QZY). [10] iii)Homologiemodell von BenI.…”