Mycobacterium tuberculosis causes nine million new active infections globally each year and led to 1.5 million deaths in 2014. Half a million of the global annual M. tuberculosis cases are estimated to be multidrug- resistant (MDR) or extensively drug resistant (XDR), and it is expected that MDR infections will only increase in prevalence. The current second-line agents used to treat MDR- and XDR-M. tuberculosis fail in more than half of cases. Resistance to front-line agents and a lack of effective, non-toxic second-line agents leaves a large unmet need for robust, fast-acting antitubercular drugs. Our laboratory has previously developed salicyl-AMS, a rationally designed intermediate analog of the aryl adenylation enzyme MbtA. Salicyl-AMS has low nanomolar biochemical inhibitory activity, sub-micromolar antimicrobial activity, and in vivo efficacy. These properties make salicyl-AMS attractive as a novel antibiotic. However, salicyl-AMS currently suffers from rapid clearance, low oral bioavailability, and modest mycobacterial wall permeability. The objective of this project is to optimize this lead compound to develop more potent and drug-like inhibitors with improved physicochemical properties. We will synthesize salicyl-AMS analogs with superior physiochemical parameters through the development of more lipophilic analogs, deletion of heteroatoms, and exploration of non-anionic linker analogs. We will then test these analogs in biochemical and cellular assays in collaboration with the laboratories of Dr. Luis Quadri (Brooklyn College) and Dr. William Bishai (John Hopkins University) for binding affinity, in vitro bacterial growth inhibition and sterilizing capability, mammalian cell cytotoxicity, and mycobacterial wall permeability.13,14 Active analogs will be tested for in vitro pharmacology (Sai Life Sciences) and in vivo pharmacokinetics in collaboration with Dr. Elisa de Stanchina (Memorial Sloan Kettering). We will then use salicyl-AMS and optimized analogs to test the hypothesis that bacteria develop resistance to inhibitors of the biosynthesis of essential ?communal goods? at a lower frequency than traditional antibiotics. If successful, the research proposed herein should result in potent, effective, nontoxic lead compounds for further preclinical development of novel antitubercular drugs. These compounds can probe the propensity of bacteria to develop resistance to drugs that inhibit the biosynthesis of essential communal goods, providing evidence regarding the communal goods/decreased resistance hypothesis. The design strategy for the inhibitors proposed herein can be translated to inhibitor design for additional adenylation enzymes, a large and untapped family of potential antibacterial targets.

Public Health Relevance

Mycobacterium tuberculosis causes nine million new active infections globally per year and led to 1.5 million deaths in 2014. The objective of this project is to optimize the Tan laboratory?s lead antitubercular compound, salicyl-AMS, to develop more potent and drug-like inhibitors with improved pharmacological properties. These optimized analogs will be evaluated for antitubercular activity in future pre-clinical and ultimately clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI129244-02
Application #
9546392
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcbride, Andre
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065