biostudies-literatureDam SM?tropole Europ?enne de LilleFrench StateAgence Nationale de la RechercheConseil R?gional Hauts-de-FranceEuropean Regional Development Fund16651-16664https://www.ebi.ac.uk/biostudies/studies/S-EPMC9791652biostudies-literatureUnknown65(24)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 <i>Mycobacterium tuberculosis</i>. 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 ATPJournal of medicinal chemistryTricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases.PMC9791652ANR-16-IDEX-0004 ULNEANR-19-CE18-0034-012020_ESR_06200028422017_ESR_14NP0020070180061762020-R3-CTRL_IPL_Phase42018-R3-CTRL-Phase2Deprez BWilland NEveque MVillemagne BPiveteau CDam SHartkoorn RCFaion LKremer LHerledan AAntoine RCarre PFlipo MLeroux FHattabi THamela CTangara SfalseTricyclic 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 <i>Mycobacterium tuberculosis</i>. 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 ATP2022-01-01T00:00:00Z2022 Dec2025-04-05T08:46:58.749Z2024-11-08T13:27:52.788ZS-EPMC97916523647369910.1021/acs.jmedchem.2c01493