MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature

Abstract

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.

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

“…The patent literature on a drug provides information about the inventions and innovations related to a drug. This information helps develop other drug inventions [74,75]. Our patent literature search provided different inventions related to Trofinetide (Table 5).…”

Structure–Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

“…Over the past 50 years, there were only four new drugs, bedaquiline, delamanid, pretomanid, and linezonid, approved for the treatment of drug-resistant TB. Currently, only SQ109, an inhibitor of membrane transporter protein MmpL3, is being evaluated in phase III, while other candidates are distributed in early clinical stages. Meanwhile, the targets of clinical candidates mainly focus on adenosine triphosphate (ATP) synthase (sudapyridine, TBAJ-876, TBAJ-587), 50S ribosomal subunit (delpazolid, sutezolid, TBI-223), and decaprenylphosphoryl- β - d -ribose 2′-epimerase (DprE: TBA-7371, PBTZ-169, BTZ-043, OPC-167832).…”

Discovery of New Isoniazid Derivatives As Anti-tubercular Agents: In silico Studies, Synthesis, and In vitro Activity Evaluation

“…TB cure needs long-term treatment (about 4-6 months) with anti-TB drugs like isoniazid (INH), pyrazinamide (PYZ), rifampin, ethambutol, and ethionamide (ETH). The chronic use of most existing treatments causes patient non-compliance, leading to drug-related toxicity (hepatotoxicity) and the development of drug resistance 4,5 . Accordingly, scientists are striving to identify new drug targets (DprE1 and MmpL3) and chemical templates for developing better, safer, and more effective TB drugs with shorter treatment duration 1,[4][5][6][7] .…”

“…The chronic use of most existing treatments causes patient non-compliance, leading to drug-related toxicity (hepatotoxicity) and the development of drug resistance 4,5 . Accordingly, scientists are striving to identify new drug targets (DprE1 and MmpL3) and chemical templates for developing better, safer, and more effective TB drugs with shorter treatment duration 1,[4][5][6][7] . DprE1 enzyme is an important drug target to combat drug resistance issues 1,2 .…”