The pipeline of new molecules and regimens against drug-resistant tuberculosis

Black, Todd A.; Buchwald, Ulrike K.

doi:10.1016/j.jctube.2021.100285

Cited by 35 publications

(32 citation statements)

References 72 publications

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“…It also highlights other anti-TB drug targets (TrmD, Ag85C, GyrB, and ClpC1). [22] Briefly explains clinical study data (NCT01785186) of SQ109 (an MmpL3 inhibitor) and comments on the improved anti-TB activity of SQ109 with MDR regimens.…”

Section: Literature On Mmpl3 Inhibitorsmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Literature On Mmpl3 Inhibitorsmentioning

confidence: 99%

“…Accordingly, this study is silent about the data of the SQ109 monotherapy. However, the 2b study advocated enhanced activity of SQ109 when added to the MDR regimen [ 22 ]. In another published study [ 33 ], TB patients were treated with SQ109, RIF, and a combination of RIF and SQ109 for 14 days.…”

Section: Sq109mentioning

confidence: 99%

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

et al. 2022

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“…Eight drugs in phase II clinical trials include SQ109 21 , GamTBvac 22 , LCB01-0371 23 , TBI-166 24 , vaccine 692342, Interferon Gamma 25 , thalidomide 26 , and metronidazole 27 . Drugs in phase III clinical trials include sutezolid 28 , tedizolid 29 , FS-1 30 , rifabutin 31 , and clarithromycin 32 . And 12 drugs have been approved in the market including isoniazid 33 , rifampicin 34 , pyrazinamide 35 , ethambutol 36 , kanamycin 37 , amikacin 38 , capreomycin 39 , levofloxacin 40 , ethylthiamine 41 , cycloserine 42 , bedaquiline 35 , and delamanid 43 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

Kuang

Zhang

Wang

et al. 2022

Acta Pharmaceutica Sinica B

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“…Treatment of XDR-TB or complicated MDR-TB has historically been lengthy and complex, requiring a combination of as many as seven antibiotics, some involving daily injections, for 18-months or longer [6] , [7] . The recent approvals of bedaquiline, delamanid, and pretomanid over the past decade, along with the repurposing of linezolid as an antituberculosis drug, have been major steps forward for the management of drug-resistant TB, enabling all-oral treatment regimens, including some of significantly shorter duration and improved treatment success [8] . Bedaquiline and delamanid were approved as add-ons to current, complex MDR-TB regimens, whereas pretomanid was approved in the specific context of a novel 3-drug, all oral regimen (BPaL), exemplifying a new approach to TB treatment development [8] .…”

Section: Introductionmentioning

confidence: 99%

“…The recent approvals of bedaquiline, delamanid, and pretomanid over the past decade, along with the repurposing of linezolid as an antituberculosis drug, have been major steps forward for the management of drug-resistant TB, enabling all-oral treatment regimens, including some of significantly shorter duration and improved treatment success [8] . Bedaquiline and delamanid were approved as add-ons to current, complex MDR-TB regimens, whereas pretomanid was approved in the specific context of a novel 3-drug, all oral regimen (BPaL), exemplifying a new approach to TB treatment development [8] . The BPaL regimen successfully treated 90% of XDR-TB and complicated MDR-TB after 6 months of treatment, which is comparable to outcomes with the standard of care for drug-sensitive TB [7] .…”

Section: Introductionmentioning

confidence: 99%

Toxicity and toxicokinetic assessment of an anti-tubercular drug pretomanid in cynomolgus monkeys

Bruning-Barry

Ambroso

Dillberger³

et al. 2022

Toxicology Reports

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The pipeline of new molecules and regimens against drug-resistant tuberculosis

Cited by 35 publications

References 72 publications

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

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

Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

Toxicity and toxicokinetic assessment of an anti-tubercular drug pretomanid in cynomolgus monkeys

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