*2.1. NADH Dehydrogenases*

*M. tb* possesses three membrane-bound NADH dehydrogenases that are capable of transferring electrons to MK with the oxidation of NADH to NAD+. There is a proton-translocating type I NADH dehydrogenase (NDH-1) and two non-proton-translocating type II NADH dehydrogenases (NDH-2) [28]. NDH-2 has been chemically validated as a drug target in *M. tb* [28–30]. Unlike NDH-1, it is absent in the mammalian genome, which is an advantage to develop specific inhibitors. NDH-1 is encoded by the nuo operon, NuoA-NuoN, (rv3145-rv3158) and the two NDH-2 are identified as Ndh (encoded by ndh = rv1854c) and NdhA (encoded by ndhA = rv0392c) [17,28]. High-throughput transposon mutagenesis studies suggested that NDH-1 and NdhA are dispensable for growth, whereas Ndh is essential in vitro and in vivo [31–33]. However, recent studies have clarified the redundancy and essentiality of the NADH dehydrogenases. Detailed gene-deletion and gene-silencing studies of nuo, ndh, and ndhA performed by Vilcheze et al., established that individually, none of the NADH dehydrogenases are essential in vitro or in vivo [34]. Beites et al. further demonstrated that NDH-2 enzymes are jointly essential for growth in the presence of long-chain fatty acids, but are dispensable for growth on some carbon sources such as glycerol [35]. Moreover, a strain deficient for NDH-2 activity is only mildly attenuated in mice [35]. Both studies agree that while *M. tb* requires at least one non-proton-pumping NDH-2 enzyme for growth, chemically targeting NDH-2 alone will likely be inefficacious, but is conceivable as part of a rational drug combination.
