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Tuberculosis (TB) is accountable for considerable global morbidity and mortality. Effective TB therapy with multiple drugs completes in about six months. The longer duration of TB therapy challenges patient compliance and contributes to treatment collapse and drug resistance (DR) progress. Therefore, new medications with an innovative mechanism of action are desperately required to shorten the TB therapy’s duration and effective TB control. The mycobacterial membrane protein Large 3 (MmpL3) is a novel, mycobacteria-conserved and recognized promiscuous drug target used in the development of better treatments for multi-drug resistance TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). This article spotlights MmpL3, the clinical studies of its inhibitor (SQ109), and the patent literature. The literature on MmpL3 inhibitors was searched on PubMed and freely available patent databases (Espacenet, USPTO, and PatentScope). SQ109, an analog of ethambutol (EMB), is an established MmpL3 inhibitor and has completed Phase 2b-3 clinical trials. Infectex and Sequella are developing orally active SQ109 in partnership to treat MDR pulmonary TB. SQ109 has demonstrated activity against drug-sensitive (DS) and drug-resistant (DR) Mycobacterium tuberculosis (Mtb) and a synergistic effect with isoniazid (INH), rifampicin (RIF), clofazimine (CFZ), and bedaquiline (BNQ). The combination of SQ109, clofazimine, bedaquiline, and pyrazinamide (PZA) has been patented due to its excellent anti-TB activity against MDR-TB, XDR-TB, and latent-TB. The combinations of SQ109 with other anti-TB drugs (chloroquine, hydroxychloroquine, and sutezolid) have also been claimed in the patent literature. SQ109 is more potent than EMB and could substitute EMB in the intensive stage of TB treatment with the three- or four-drug combination. Developing MmpL3 inhibitors is a promising approach to fighting the challenges associated with DS-TB and DR-TB. The authors foresee MmpL3 inhibitors such as SQ109 as future drugs for TB treatment.

SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of Leishmania, Trypanosoma spp. as well as Toxoplasma infection. In the T. cruzi mouse model, 80% of SQ109-treated mice survived at 40 days post-infection. Even though SQ109 did not cure all mice, these results are of interest since they provide a basis for future testing of combination therapies with the azole posaconazole, which acts synergistically with SQ109 in vitro. We also found that SQ109 inhibited the growth of Toxoplasma gondii in vitro with an IC50 of 1.82 µM and there was an 80% survival in mice treated with SQ109, whereas all untreated animals died 10 days post-infection. Results with Trypanosoma brucei and Leishmania donovani infected mice were not promising with only moderate efficacy. Since SQ109 is known to be extensively metabolized in animals, we investigated the activity in vitro of SQ109 metabolites. Among 16 metabolites, six mono-oxygenated forms were found active across the tested protozoan parasites, and there was a ~6× average decrease in activity of the metabolites as compared to SQ109 which is smaller than the ~25× found with mycobacteria.

Mycobacterium tuberculosis (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. This includes targeting NADH dehydrogenase by phenothiazine derivatives, menaquinone biosynthesis by DG70 and other compounds, terminal oxidase by imidazopyridine amides and ATP synthase by diarylquinolines. Importantly, oxidative phosphorylation also plays a critical role in the survival of persisters. Thus, inhibitors of oxidative phosphorylation can synergize with frontline TB drugs to shorten the course of treatment. In this review, we discuss the oxidative phosphorylation pathway and development of its inhibitors in detail.