Methionine aminopeptidases from Mycobacterium tuberculosis as novel antimycobacterial targets.
Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Omonike
O
Olaleye
Tirumalai R
TR
Raghunand
Shridhar
S
Bhat
Jian
J
He
Sandeep
S
Tyagi
Gyanu
G
Lamichhane
Peihua
P
Gu
Jiangbing
J
Zhou
Ying
Y
Zhang
Jacques
J
Grosset
William R
WR
Bishai
Jun O
JO
Liu
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D063208:Methionyl Aminopeptidases; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000254:growth & development; D016415:Sequence Alignment; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases