Research Projects

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease causing approximately 1.5 million deaths annually. The emergence of drug-resistant strains and limited anti-TB drugs necessitate the discovery of novel drug targets. Mtb requires oxygen for growth, and the absence of oxygen triggers a transition from actively growing to a drug-tolerant non-replicating persistent state. The aerobic lifestyle in Mtb generates endogenous Reactive Oxygen Species (eROS), which can cause oxidative injury to DNA, proteins, and lipids. Mtb is sensitive to cell-permeable molecules that disrupt redox homeostasis by artificially elevating eROS inside cells. Mtb also elevates the expression of certain metabolic pathways to maintain redox balance and tolerating anti-TB drugs inside macrophages. These findings highlight the need for a comprehensive genomic-level understanding of redox homeostasis in Mtb. A global understanding of redox homeostasis in Mtb will shed new light on disease biology and reveal pathways that can be targeted to potentiate existing drugs by disrupting redox homeostasis and increasing eROS in Mtb. To achieve this, a Himar1-based saturated Tn mutant library will be built in Mtb expressing Mrx1-roGFP2 (strain Mtb-roGFP2), and a next-generation sequencing (NGS) and analysis pipeline will be developed to construct a system-level network of genetic factors essential for maintaining redox homeostasis under aerobic growth in Mtb. The technology developed and findings of this proposal will significantly contribute to the dissection of Mtb redox pathways and impact drug discovery approaches.