Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases

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.