## 3 Overview of the Inhibitors Targeting the OxPhos Pathway
### Inhibitors of the Cyt-bcc-aa3 Complex
Imidazopyridine ethers (IPEs) were identified from a biochemical screen of AstraZeneca's corporate compound collection aimed at identifying inhibitors of ATP homeostasis [128]. The extent of ATP synthesis inhibition, as measured in IMV of _M. smeg_, correlated well with anti-tubercular potency in _M. tb_, with a MIC of 0.03 mM for some optimised derivatives [128]. While generating resistant mutants to the series was unsuccessful, target site deconvolution through a series of biochemical tests and cell-based assays indicated that these chemical entities target the Cyt-bcc-aa3 complex. These series have been deprioritised by the group due to their poor solubility and poor PK profile [128]. Structurally similar to the IPs, the pyrazolopyridine carboxamide series were designed as novel anti-tubercular agents through a scaffold hopping strategy [149; 147]. The lead compound, TB-47, is currently in early-stage development. It has activity against replicating _M. tb_ in vitro with MICs of 0.016 to 0.5 mg/mL when tested against a panel of _M. tb_ drug-susceptible and drug-resistant \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Chemical Class** & **Represented by** & **Structure** & **Ref** \\ \hline
2-Ethylthio-4-methylaminoquinazolines & 11726148 & & [78] \\ \hline  & & **Cyt-bd inhibitor** & \\ \hline Aurachin D & & [137] \\ \hline \hline \end{tabular}
\end{table} 
Table 3: _Cont._clinical isolates, and a high-selective index. Furthermore, TB-47 is well-tolerated and has good oral bioavailability in rats. While it did not display bactericidal activity alone in mouse models of acute and chronic TB infection, TB-47 potentiated the activity of pyrazinamide (PZA) and RIF during an acute TB infection in mice [128]. The authors speculated that alteration of the NADH/NAD\({}^{+}\) ratio triggered by QcrB inhibition sensitized the bacteria to the front-line drugs. While this hypothesis is interesting, it remains to be further explored since no positive interactions between RIF and the QcrB inhibitor Q203 in vitro have been observed [150]. Resistant mutants to TB-47 were generated in a _M. smeg_ strain with a deletion of Cyt-bd oxidase, and whole-genome sequencing of the isolates revealed mutation H190Y in QcrB of _M. smeg_[128]. This residue, equivalent to H195 in _M. tb_, is located in the cd2 loop of QcrB, which is thought to interact with the Qp site [128]. A host cell-based screen of FDA-approved drugs of the Prestwick chemical library for compounds that protect lung fibroblasts from _M. tb_-induced cytotoxicity identified the gastric proton-pump inhibitor, lansoprazole (LPZ, Prevacid), as a potent hit compound [129]. LPZ is a prodrug that requires the host cell environment for conversion into lansoprazole sulphide (LPZS). Oral administration of LPZS significantly reduced bacterial burden during an acute TB infection in mice, and the compound lacks cytotoxicity, being well-tolerated in mice at a dose of 300 mg/kg. Whole-genome sequencing of resistant mutants generated to LPZS revealed mutation L176P in QcrB, and cross-resistance studies with imidazopyridine amide compounds and the T313A mutant strain indicated a distinct binding mode [129]. A follow-up study demonstrated that when LPZ is administered orally or intraperitoneally (i.p.) to rats, conversion to the active metabolite LPZS is undetectable in plasma and lung tissue, whereas LPZS was highly stable after i.p. administration [151]. In spite of this, LPZ intake has been found to significantly protect against TB incidence in individuals based on a cohort study conducted using the United Kingdom Clinical Practice Research Datalink [152]. The phenoxyalkylbenzimidazole (PAB) series, with an excellent growth-inhibitory potency and low cytotoxicity, is another promising QcrB inhibitor [130; 153]. The lead compound, 54, demonstrated good efficacy against intracellular _M. tb_. Resistant mutants to PAB isolated in _M. tb_ revealed mutations in qcrB and rv1339, a gene of unknown function.