## 3 Overview of the Inhibitors Targeting the OxPhos Pathway
### Inhibitors of the Cyt-bcc-aa3 Complex  
A number of chemically-diverse and distinct scaffolds target the _M. tb_ cytochrome bcc oxidase by binding at the Qp site of the QcrB subunit, otherwise known as the stigmatellin pocket. The Qp site is one of two quinol catalytic sites on QcrB. The promiscuous nature of this target has been attributed to its localization in the bacterial membrane, as with other membrane-associated targets [54, 68]. In this section, we provide an overview of chemical classes reported to inhibit the Cyt-bcc-aa3 terminal oxidase (Table 3). \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Chemical Class** & **Represented by** & **Structure** & **Ref** \\ \hline \multicolumn{4}{c}{**Cytochrome bcc inhibitors**} \\ \hline Imidazopyridines & Q203 (Telacebec) & & [12] \\ \hline Imidazo[2,1-b]thiazole-5 -carboxamide & ND-11543 & & [126] \\ \hline Imidazopyridine ethers & 19e & & [127] \\ \hline Pyrazol[1,5-a]pyridine-3- -carboxamide & TB47 & & [128] \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Inhibitors of the Cyt-bcc-aa3 complex and the bd oxidase discussed in this review. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Chemical Class** & **Represented by** & **Structure** & **Ref** \\ \hline Lansoprazole sulphide (LPZS) & & & \\ Phenoxyalkylbenzimidazole & 54 & & \\ Pyrrolo[  
Several promising hits belonging to the chemical class of imidazopyridines (IPs) have been identified in independent screening programs [12; 137; 138; 139; 140; 141; 142; 143]. Extensive efforts have been undertaken to optimise and to explore the SAR of this scaffold [144; 145; 146; 147; 148; 149; 140; 143]. To date, the most advanced QcrB inhibitor is Q203, an IP derivative in Phase 2 clinical trials. The drug candidate was initially discovered in a phenotypic high-content screen in _M. tb_-infected macrophages and further optimised to achieve an MIC\({}_{50}\) of 2.7 nM against _M. tb_ H37 Rv in vitro. Its activity is comparable to that of BDQ and INH in a mouse model of chronic TB infection [12]. In addition to its potency, the positive results from the Phase 1 and Phase 2a early bactericidal activity clinical trial indicate its safety and tolerability in TB patients, emphasizing the specificity of bacterial inhibition without affecting the human counterpart [145]. Resistant mutants generated to Q203 revealed amino acid mutations T313A or T313I in QcrB [12]. This interaction between Q203 and QcrB has recently been biochemically demonstrated by in-cell NMR using whole _M. smeg_ cells expressing the _M. tb_ QcrCAB complex and a Q203 derivative, indicating target engagement at the Qp site of QcrB [146]. While bacteriostatic on its own in _M. tb_, Q203 becomes highly bactericidal when the alternate Cyt-bd oxidase is absent, as demonstrated in _M. tb_-infected macrophages and in a mouse model of acute TB infection [147; 66]. Q203 is also highly bactericidal and potent against _Mycobacterium ulcerans_, reducing bacterial load in a mouse footpad infection model of Buruli ulcer by 99.99% at a dose of 0.5 mg/kg administered three times per week for four weeks [148]. This highlights additional opportunities for repurposing QcrB inhibitors against other organisms that do not harbour functional alternative terminal oxidases, such as _M. ulcerans_ and _Mycobacterium leprae_. Extended SAR studies of IPs imidazopyridine carboxamides led to the novel scaffold imidazothiazole carboxamides (ITA), of which analogues have nanomolar potency (MIC \(<\) 10 nM) against replicating and drug-resistant _M. tb_[144]. Derivatives of this class also demonstrate intracellular activity in macrophages and in vivo [144]. Additionally, cross-resistance studies with strains harbouring QcrB mutations and dose-response studies in a _M. tb_ strain without Cyt-bd oxidase indicate that these compounds target QcrB [144]. This series is promising for its tolerability and good oral bioavailability in mice [127].