Development of 1,2,4-triazolyl compounds and their derivatives as a new treatment for tuberculosis
Active Project Grant Awarded Last action
- Award ID
- R01AI181316
- Recipient
-
The Washington University UEI L6NFUM28LQM5
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,278,263
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 46% complete
- Place of performance
- St. Louis, MO 63110, USA
Award details come from USAspending.gov.
Description
- Abstract
- Mycobacterium tuberculosis (MTB) caused an estimated 1.6 million deaths in 2021. The emergence of drug- resistant strains has exacerbated the epidemic, often rendering existing tuberculosis (TB) therapies inadequate and revealing the dire need for new agents with unique mechanisms of action to combat the epidemic. Towards this end, we have identified a new series of nitro-containing 1,2,4-triazole compounds that are potent inhibitors of MTB. Our preliminary data show that the nitro 1,2,4-triazoles retain activity in MTB strains that are resistant to the frontline antibiotics isoniazid and rifampicin, as well as moxifloxacin. In addition, we provide data that argues against the nitro 1,2,4-triazoles inhibiting qcrb and MMPL3, two proteins commonly targeted by compounds identified in phenotypic screens in MTB. Thus, IT is possible that the nitro 1,2,4-triazole series represents a new mechanism of action (MOA) for inhibition of MTB. To begin to investigate how the nitro-1,2,4-triazoles inhibit MTB, we selected for resistant mutants and identified resistant isolates with mutations in genes required for coenzyme F420 biosynthesis and the nitroreductase DDN. These mutants are also resistant to pretomanid, a prodrug that requires activation of its aromatic nitro group by F420-dependent-DDN activity in order to exert anti-MTB activity. We predicted that our nitro 1,2,4-triazoles are similarly activated by DDN. Therefore, in an effort to circumvent the need for activation, we performed structure activity relationship (SAR) analyses and discovered that replacement of the nitro groups in the phenyl ring on the 1,2,4-triazole core with chloro retained activity against WT MTB and avoided loss of activity in F420 and DDN mutants. Thus, the chloro-containing 1,2,4-triazoles circumvent the predominant resistance mechanism against aromatic nitro-containing compounds. We also examined core modifications that would retain anti-MTB activity and discovered that the 1,2,4-triazole core can be replaced with a chiral pyrrolidine core and retain the same activity. This led US to hypothesize that the core is a "spacer" linking the other parts of the molecule. Since the core structure defines the compound class, our SAR method has now resulted in a second new class anti-MTB agents that will act as a bioisostere with similar steric volume and retained hydrogen-bond donor/acceptor atoms as the 1,2,4-triazole series. The increased SP3 character of the pyrrolidine scaffolds could be advantageous over the 1,2,4-triazole scaffold in terms of a more diverse chemical space that has been shown to translate to enhanced clinical success. Our objectives are to demonstrate preclinical proof-of-concept for the 1,2,4-triazole and pyrrolidine compounds to combat MTB infection and optimize lead compounds for pharmacologic properties required for translation to a therapeutic. Based on our preliminary data, we hypothesize that the 1,2,4-triazole and pyrrolidine compounds operate through a unique MOA as compared to other antibiotics and, therefore, dissecting their mode of inhibition will also reveal new biological insight into MTB physiology and pathogenesis.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $745,546 | |
| Amendment | $745,546 | |
| Original award | $787,171 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Trustees Of Tufts College | $148,842 | |
| The University Of Mississippi | $140,511 | |
| University Of Tennessee | $617,306 |
Quick answers
Who received award R01AI181316?
R01AI181316 was awarded to The Washington University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 1, 2024.
How much is award R01AI181316 worth?
$2,278,263 has been obligated on R01AI181316.
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