{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T11:12:13Z","timestamp":1762254733102,"version":"3.41.2"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["P01AI143575, 1 R21 AI168506-01A1"],"award-info":[{"award-number":["P01AI143575, 1 R21 AI168506-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2023,12,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Type 2 NADH dehydrogenase (Ndh-2) is an oxidative phosphorylation enzyme discussed as a promising drug target in different pathogens, including\n            <jats:italic>Plasmodium falciparum<\/jats:italic>\n            and\n            <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n            (\n            <jats:italic>Mtb<\/jats:italic>\n            ). To kill\n            <jats:italic>Mtb<\/jats:italic>\n            , Ndh-2 needs to be inactivated together with the alternative enzyme type 1 NADH dehydrogenase (Ndh-1), but the mechanism of this synthetic lethality remained unknown. Here, we provide insights into the biology of NADH dehydrogenases and a mechanistic explanation for Ndh-1 and Ndh-2 synthetic lethality in\n            <jats:italic>Mtb<\/jats:italic>\n            . NADH dehydrogenases have two main functions: maintaining an appropriate NADH\/NAD+ ratio by converting NADH into NAD+ and providing electrons to the respiratory chain. Heterologous expression of a water-forming NADH oxidase (Nox), which catalyzes the oxidation of NADH, allows us to distinguish between these two functions and shows that Nox rescues\n            <jats:italic>Mtb<\/jats:italic>\n            from Ndh-1\/Ndh-2 synthetic lethality, indicating that NADH oxidation is the essential function of NADH dehydrogenases for\n            <jats:italic>Mtb<\/jats:italic>\n            viability. Quantification of intracellular levels of NADH, NAD, ATP, and oxygen consumption revealed that preventing NADH oxidation by Ndh-1\/Ndh-2 depletes NAD(H) and inhibits respiration. Finally, we show that Ndh-1\/Ndh-2 synthetic lethality can be achieved through chemical inhibition.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              In 2022, it was estimated that 10.6 million people fell ill, and 1.6 million people died from tuberculosis (TB). Available treatment is lengthy and requires a multi-drug regimen, which calls for new strategies to cure\n              <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n              (\n              <jats:italic>Mtb<\/jats:italic>\n              ) infections more efficiently. We have previously shown that simultaneous inactivation of type 1 (Ndh-1) and type 2 (Ndh-2) NADH dehydrogenases kills\n              <jats:italic>Mtb<\/jats:italic>\n              . NADH dehydrogenases play two main physiological roles: NADH oxidation and electron entry into the respiratory chain. Here, we show that this bactericidal effect is a consequence of impaired NADH oxidation. Importantly, we demonstrate that Ndh-1\/Ndh-2 synthetic lethality can be achieved through simultaneous chemical inhibition, which could be exploited by TB drug development programs.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01045-23","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T14:01:49Z","timestamp":1701352909000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["Synthetic lethality of\n            <i>Mycobacterium tuberculosis<\/i>\n            NADH dehydrogenases is due to impaired NADH oxidation"],"prefix":"10.1128","volume":"14","author":[{"given":"Yuanyuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medical College, New York, 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