Grants and Contracts Details
Description
Tuberculosis (TB) is the deadliest global infection (1.4 million deaths in 2015), having recently surpassed
HIV/AIDS. ~250,000 of these deaths were from multidrug-resistant (MDR) TB, with only ~50% success
in treatment of MDR-TB. Unless new strategies to combat or prevent emergence of drug-resistant TB are
found, the global spread of MDR-Tb will be an epidemic of epic proportions. Kanamycin A (KAN) is an
antibiotic of last resort used to treat MDR-TB. Resistance to KAN signifies extensively drug-resistant
(XDR) TB, which is nearly incurable. One-third of KAN-resistant TB is caused by upregulation of the
acetyltransferase Eis in Mycobacterium tuberculosis (Mtb), caused by mutations in the eis promoter. We
investigated the mechanism of Eis and discovered and validated several Eis inhibitor scaffolds in the
previous funding period. In Aim 1 of this application, we propose to develop a novel strategy to combat
and forestall KAN resistance in TB. This Aim is focused on the preclinical development of these Eis
inhibitors for their ultimate use as a combination therapy with KAN against MDR-TB. In Aim 2, we propose
to determine the mechanism of the anti-Mtb activity of novel compounds that were discovered to inhibit
Eis and potently inhibit Mtb bacteria without KAN, ultimately to develop them as therapeutics against both
drug-resistant and drug-resistant TB.
Status | Finished |
---|---|
Effective start/end date | 8/1/11 → 5/31/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $2,727,653.00
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