Systematic exploitation of synergy to improve tuberculosis therapy.

Summary. Systematic exploitation of synergy to improve tuberculosis therapy. The mycobacterial cell wall is a complex and interdependent structure that is essential for viability and is a validated target for antimicrobial agents. In addition, this structure represents the primary barrier limiting the access of chemical inhibitors to their targets, reducing the efficacy of existing drugs and impeding the development of new agents. Targeting the cell wall in combination drug therapy increases permeability and has become standard treatment for diverse fungal and bacterial pathogens. Thus, the mycobacterial cell wall represents a rich source of targets for the development of synergistic inhibitors that either enhance the penetration of other agents, or simultaneous disrupt partially compensatory structural components. This project will use a chemical genetic approach to identify cell wall metabolic proteins that can be inhibited to produce synergistic effects with existing antimicrobials, leverage structure-guided drug design to produce specific chemical inhibitors and combine these methods to investigate both the mechanisms underlying synergy and test the effect of combination therapy during infection. The aspirational goal of this work is the design of new strategies to accelerate tuberculosis combination therapy. Project Number: 1R01AI189852-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: JAMES SACCHETTINI (+1 co-PI) | Institution: TEXAS A&M AGRILIFE RESEARCH, College Station, TX | Award Amount: $698,387 | Activity Code: R01 | Study Section: Drug Discovery and Molecular Pharmacology A Study Section [DMPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18985201A1