Abstract

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 Aims 1 and 2 of this application, we propose to develop a novel strategy to combat and forestall KAN resistance in TB.
These Aims are focused on the preclinical development of these Eis inhibitors for their ultimate use as a combination therapy with KAN against MDR-TB.
In Aim 3, we propose to determine the mechanism(s) 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.

Public Health Relevance

Tuberculosis (TB) kills 1.4 million annually worldwide and is currently the deadliest infection with ~250,000 of these deaths resulting from multidrug-resistant (MDR) TB, for which the treatment success rate is only 50%. This project is focused on developing innovative kanamycin adjuvants (Eis inhibitors) for their use with kanamycin to forestall and combat MDR-TB. Additionally, the project is focused on elucidating the mechanism and development of other novel anti-TB agents to kill the pathogenic mycobacteria without the need of using KAN, ultimately to develop these agents as therapeutics against both drug-resistant and drug-resistant TB in the US and worldwide.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI090048-08
Application #
9709207
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xu, Zuoyu
Project Start
2011-08-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526

  Publications

Louzoun Zada, Sivan; Green, Keith D; Shrestha, Sanjib K et al. (2018) Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall. ACS Infect Dis 4:1121-1129
Holbrook, Selina Y L; Gentry, Matthew S; Tsodikov, Oleg V et al. (2018) Nucleoside triphosphate cosubstrates control the substrate profile and efficiency of aminoglycoside 3'-O-phosphotransferase type IIa. Medchemcomm 9:1332-1339
Holbrook, Selina Y L; Garneau-Tsodikova, Sylvie (2018) Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates. Microb Drug Resist 24:1020-1030
Green, Keith D; Biswas, Tapan; Pang, Allan H et al. (2018) Acetylation by Eis and Deacetylation by Rv1151c of Mycobacterium tuberculosis HupB: Biochemical and Structural Insight. Biochemistry 57:781-790
Thamban Chandrika, Nishad; Shrestha, Sanjib K; Ranjan, Nihar et al. (2018) New Application of Neomycin B-Bisbenzimidazole Hybrids as Antifungal Agents. ACS Infect Dis 4:196-207
Thamban Chandrika, Nishad; Shrestha, Sanjib K; Ngo, Huy X et al. (2018) Novel fluconazole derivatives with promising antifungal activity. Bioorg Med Chem 26:573-580
Thamban Chandrika, Nishad; Shrestha, Sanjib K; Ngo, Huy X et al. (2018) Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents. J Med Chem 61:158-173
Ngo, Huy X; Green, Keith D; Gajadeera, Chathurada S et al. (2018) Potent 1,2,4-Triazino[5,6 b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis. ACS Infect Dis 4:1030-1040
Thamban Chandrika, Nishad; Garneau-Tsodikova, Sylvie (2018) Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities. Chem Soc Rev 47:1189-1249
Fosso, Marina Y; Shrestha, Sanjib K; Thamban Chandrika, Nishad et al. (2018) Differential Effects of Linkers on the Activity of Amphiphilic Tobramycin Antifungals. Molecules 23:

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