{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dam S"],"funding":["M?tropole Europ?enne de Lille","French State","Agence Nationale de la Recherche","Conseil R?gional Hauts-de-France","European Regional Development Fund"],"pagination":["16651-16664"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9791652"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["65(24)"],"pubmed_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 <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<sup>+</sup> ratios and decreased ATP"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases."],"pmcid":["PMC9791652"],"funding_grant_id":["ANR-16-IDEX-0004 ULNE","ANR-19-CE18-0034-01","2020_ESR_06","20002842","2017_ESR_14","NP0020070","18006176","2020-R3-CTRL_IPL_Phase4","2018-R3-CTRL-Phase2"],"pubmed_authors":["Deprez B","Willand N","Eveque M","Villemagne B","Piveteau C","Dam S","Hartkoorn RC","Faion L","Kremer L","Herledan A","Antoine R","Carre P","Flipo M","Leroux F","Hattabi T","Hamela C","Tangara S"],"additional_accession":[]},"is_claimable":false,"name":"Tricyclic SpiroLactams Kill Mycobacteria In Vitro and In Vivo by Inhibiting Type II NADH Dehydrogenases.","description":"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<sup>+</sup> ratios and decreased ATP","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2025-04-05T08:46:58.749Z","creation":"2024-11-08T13:27:52.788Z"},"accession":"S-EPMC9791652","cross_references":{"pubmed":["36473699"],"doi":["10.1021/acs.jmedchem.2c01493"]}}