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

被引：16

作者：

Imran, Mohd. ^{[1
]}

Arora, Mandeep Kumar ^{[2
]}

Chaudhary, Anurag ^{[3
]}

Khan, Shah Alam ^{[4
]}

Kamal, Mehnaz ^{[5
]}

Alshammari, Manal Mutlaq ^{[6
]}

Alharbi, Raghad Mohammad ^{[7
]}

Althomali, Nuha Abdullah ^{[8
]}

Alzimam, Ibrahim Mohammed ^{[9
]}

Alshammari, Abdullah Ayed ^{[10
]}

Alharbi, Bashair Hamed ^{[11
]}

Alshengeti, Amer ^{[12
,13
]}

Alsaleh, Abdulmonem A. ^{[14
]}

Alqahtani, Shayea A. ^{[15
]}

Rabaan, Ali A. ^{[16
,17
,18
]}

机构：

[1] Northern Border Univ, Dept Pharmaceut Chem, Fac Pharm, Rafha 91911, Saudi Arabia

[2] DIT Univ, Sch Pharmaceut & Populat Hlth Informat, Dehra Dun 248009, Uttarakhand, India

[3] Meerut Inst Engn & Technol, Dept Pharmaceut Technol, Meerut 250005, Uttar Pradesh, India

[4] Natl Univ Sci & Technol, Coll Pharm, Dept Pharmaceut Chem, Muscat 130, Oman

[5] Prince Sattam Bin Abdulaziz Univ, Coll Pharm, Dept Pharmaceut Chem, Al Kharj 11942, Saudi Arabia

[6] Hotat Bani Tamim Gen Hosp, Pharm Dept, Hotat Bani Tamim 16631, Saudi Arabia

[7] Umm Alqura Univ, Dept Pharm, Mecca 24225, Saudi Arabia

[8] Kol Alosra, Dept Community Pharm, Taif 26512, Saudi Arabia

[9] Northern Border Univ, Fac Pharm, Rafha 91911, Saudi Arabia

[10] Nahdi Med Co, Riyadh 12211, Saudi Arabia

[11] Umm Alqura Univ, Dept Clin Pharm, Jeddah 21921, Saudi Arabia

[12] Taibah Univ, Coll Med, Dept Pediat, Al Madinah 41491, Saudi Arabia

[13] Prince Mohammad Bin Abdulaziz Hosp, Dept Infect Prevent & Control, Natl Guard Hlth Affairs, Al Madinah 41491, Saudi Arabia

[14] Mohammed Al Mana Coll Med Sci, Clin Lab Sci Dept, Dammam 34222, Saudi Arabia

[15] Erhadh Hosp, Med Lab Dept, Dammam 32434, Saudi Arabia

[16] Johns Hopkins Aramco Healthcare, Mol Diagnost Lab, Dhahran 31311, Saudi Arabia

[17] Alfaisal Univ, Coll Med, Riyadh 11533, Saudi Arabia

[18] Univ Haripur, Dept Publ Hlth & Nutr, Haripur 22610, Pakistan

来源：

BIOMEDICINES | 2022年 / 10卷 / 11期

关键词：

tuberculosis; drug-resistance; Mmpl3; SQ109; clinical studies; patent; ANTITUBERCULAR DRUG; DISCOVERY; TRANSPORTER; RIFAMPICIN; DIAGNOSIS;

D O I：

10.3390/biomedicines10112793

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 latentTB. 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.

引用

页数：15

共 2 条

[1] Inhibition Mechanism of Anti-TB Drug SQ109: Allosteric Inhibition of TMM Translocation of Mycobacterium Tuberculosis MmpL3 Transporter
Carbone, Justin
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Bennet, Lucas
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Wu, Chun
[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2023, 63 (16) : 5356 - 5374
[2] SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis
Tahlan, Kapil
Wilson, Regina
Kastrinsky, David B.
Arora, Kriti
Nair, Vinod
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Barnes, S. Whitney
Walker, John R.
Alland, David
Barry, Clifton E., III
Boshoff, Helena I.
[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2012, 56 (04) : 1797 - 1809

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