PUBLICATION
Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases
- Authors
- Dam, S., Tangara, S., Hamela, C., Hattabi, T., Faïon, L., Carre, P., Antoine, R., Herledan, A., Leroux, F., Piveteau, C., Eveque, M., Flipo, M., Deprez, B., Kremer, L., Willand, N., Villemagne, B., Hartkoorn, R.C.
- ID
- ZDB-PUB-221207-7
- Date
- 2022
- Source
- Journal of medicinal chemistry 65(24): 16651-16664 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antitubercular Agents/pharmacology
- Mycobacterium tuberculosis*
- NAD*
- NADH, NADPH Oxidoreductases
- Zebrafish
- PubMed
- 36473699 Full text @ J. Med. Chem.
Citation
Dam, S., Tangara, S., Hamela, C., Hattabi, T., Faïon, L., Carre, P., Antoine, R., Herledan, A., Leroux, F., Piveteau, C., Eveque, M., Flipo, M., Deprez, B., Kremer, L., Willand, N., Villemagne, B., Hartkoorn, R.C. (2022) Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases. Journal of medicinal chemistry. 65(24):16651-16664.
Abstract
It is critical that novel classes of antituberculosis drugs are developed to combat the increasing burden of infections by multidrug-resistant strains. To identify such a novel class of antibiotics, a chemical library of unique 3-D bioinspired molecules was explored revealing a promising, mycobacterium specific Tricyclic SpiroLactam (TriSLa) hit. Chemical optimization of the TriSLa scaffold delivered potent analogues with nanomolar activity against replicating and nonreplicating Mycobacterium tuberculosis. Characterization of isolated TriSLa-resistant mutants, and biochemical studies, found TriSLas to act as allosteric inhibitors of type II NADH dehydrogenases (Ndh-2 of the electron transport chain), resulting in an increase in bacterial NADH/NAD+ ratios and decreased ATP levels. TriSLas are chemically distinct from other inhibitors of Ndh-2 but share a dependence for fatty acids for activity. Finally, in vivo proof-of-concept studies showed TriSLas to protect zebrafish larvae from Mycobacterium marinum infection, suggesting a vulnerability of Ndh-2 inhibition in mycobacterial infections.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping