Methionine Aminopeptidases as Therapeutic Targets for Tuberculosis

The increased emergence of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb) has heightened the need for novel anti-mycobacterial agents. The lethal synergy of Mtb with HIV has made the requirement for the development of new anti-TB agents more imperative. The therapeutic management of HIV patients co-infected with Mtb poses great challenges because of drug-drug interactions and toxicity. Hence, our studies focus on targeting the role of Methionine Aminopeptidases (MetAP) in Mycobacterium tuberculosis using novel inhibitors. MetAP is a dinuclear metalloprotease that removes the N-terminal methionine from proteins and peptides. N-terminal methionine excision (NME) is important for localization, stability and post-translational modifications of some proteins. This essential role of MetAPs makes this enzyme a prospective target for the development of new therapeutic agents. The hypothesis for the proposed research is that: The development of mycobacterial MetAP inhibitors may serve as chemotherapeutic agents against infections caused by M. tuberculosis. Therefore, our research studies focus on inhibiting MetAP’s function as a biochemical tool to understand and therapeutically target TB disease. The clinical significance of this study is that, we might be able to target MetAP and treat TB patients. While at Johns Hopkins University School of Medicine, Omonike Olaleye identified potent inhibitors of MetAPs from M. tuberculosis (MtMetAP1a and MtMetAP1c) using a high-throughput screening (HTS) approach. We have successfully progressed in characterizing our lead compounds. The clinical significance of this study is that therapeutic targeting of MetAP’s function may lead to the development of novel antimycobacterials, and may accelerate the drug discovery efforts in search for agents to treat patients with drug-resistant Mtb, latent TB and TB - HIV co-infection. Moreover, these studies will give us more insight to the relevance of N-terminal protein processing in Mtb.