We are using chemical technologies to investigate Mycobacterium tuberculosis (Mtb), the bacterial pathogen that causes tuberculosis (TB). Latent TB infections infect one-third of the human population, and active TB kills 1.5 million people a year. The non-replicating, dormant bacteria associated with latent disease are phenotypically resistant to most antibiotics, making latent disease difficult to treat or cure. Approximately 10% of people with LTBI will transition to active disease, making LTBI a formidable barrier to global TB eradication. We are creating new small molecule probes and molecular imaging assays to reveal how enzymes (e.g., esterases) are regulated by Mtb in different metabolic states. We employ small molecule probes to rapidly assess and track enzyme regulation. These studies rely on both activity-based probes (ABPs) and fluorogenic probes. These probes enable us to access distinct information. For example, ABPs are covalent active-site inhibitors, and we used ABPs to enrich active serine hydrolases from metabolically distinct samples. By comparison, our fluorogenic probes are sensitive turn-over substrates for monitoring sub-groups of enzymes (e.g., lipases). Both types of probe are being used to distinguish distinct esterase activities in dormant and active Mtb. Our long-term goal is to identify mycobacterial hydrolases that can be exploited for therapeutics or for detecting TB in simple point-of-care diagnostic assays.

Chemical technologies for illuminating Mycobacterium tuberculosis

253rd National Meeting (2017)

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