Mycobacterium tuberculosis (Mtb) is a causative agent of tuberculosis (TB), faces a particularly unique challenge in that it resides within human. Evolutionarily, Mtb is capable of entry into a state of slowed or arrested replication. The majority of TB patients harbor this non-replicating (NR) form of Mtb that are asymptomatic and tolerant to most existing TB drugs. My laboratory thus will be focused on expanding our knowledge of the specific metabolic reprograms used by Mtb to complete its lifecycle as a source of drug targets.
- Metabolic activities essential for transition between replicating and non-replicating forms of Mtb. Mtb spends the majority of its lifetime in a state of slowed or arrested replication while remaining poised to reenter cell cycle. Remarkably, Mtb evolutionarily achieves the capacity to remodel its metabolism to complete the lifecycle.
• First, my laboratory will assess the metabolic reprogramming associated with transition between NR latency and replicating active form. To this aim, I will use isotopic tracing Liquid Chromatography Mass Spectrometry (LC-MS) metabolomics.
• Second, metabolic reprogramming during transition states requires biochemical/molecular bases which are still undefined. My laboratory will, thus, reveal the regulatory mechanisms; (i) post-translational modification of target enzymes, (ii) allosteric regulation, and (iii) condition-dependent switched interactive partners.
- Products of various stages of Mtb interactive with host innate immune system
Host immune system acts as an internal shield against invading Mtb. Thus, intervention in the host cell responses against Mtb infection should promise to expand therapeutic option.
• Invading Mtb interacts with host cells through either physical contact or indirect modulation of signaling cascades with secreted mediators. My laboratory will thus seek to establish the repertoires of key candidates by using LC-MS based glycolipidome and secreted metabolome.
The studies will lead to a better understanding of Mtb chemistry, metabolism, and pathogenicity. This could facilitate to the discovery of conceptually novel drug targets and diagnostic biomarkers to improve the quality of current TB control.