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Imran, M.;  Arora, M.K.;  Chaudhary, A.;  Khan, S.A.;  Kamal, M.;  Alshammari, M.M.;  Alharbi, R.M.;  Althomali, N.A.;  Alzimam, I.M.;  Alshammari, A.A.; et al. MmpL3 Inhibition in Thearaphy of Tuberculosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/36042 (accessed on 23 April 2024).
Imran M,  Arora MK,  Chaudhary A,  Khan SA,  Kamal M,  Alshammari MM, et al. MmpL3 Inhibition in Thearaphy of Tuberculosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/36042. Accessed April 23, 2024.
Imran, Mohd., Mandeep Kumar Arora, Anurag Chaudhary, Shah Alam Khan, Mehnaz Kamal, Manal Mutlaq Alshammari, Raghad Mohammad Alharbi, Nuha Abdullah Althomali, Ibrahim Mohammed Alzimam, Abdullah Ayed Alshammari, et al. "MmpL3 Inhibition in Thearaphy of Tuberculosis" Encyclopedia, https://encyclopedia.pub/entry/36042 (accessed April 23, 2024).
Imran, M.,  Arora, M.K.,  Chaudhary, A.,  Khan, S.A.,  Kamal, M.,  Alshammari, M.M.,  Alharbi, R.M.,  Althomali, N.A.,  Alzimam, I.M.,  Alshammari, A.A.,  Alharbi, B.H.,  Alshengeti, A.,  Alsaleh, A.A.,  Alqahtani, S.A., & Rabaan, A.A. (2022, November 23). MmpL3 Inhibition in Thearaphy of Tuberculosis. In Encyclopedia. https://encyclopedia.pub/entry/36042
Imran, Mohd., et al. "MmpL3 Inhibition in Thearaphy of Tuberculosis." Encyclopedia. Web. 23 November, 2022.
MmpL3 Inhibition in Thearaphy of Tuberculosis
Edit

Tuberculosis (TB) is a contagious bacterial illness known to humankind since ancient times. The causal microorganism of TB is Mycobacterium tuberculosis (Mtb). Lung or pulmonary TB is the most common form, but Mtb also affects other body parts. TB does not spare any age group and is omnipresent worldwide. Most TB patients remain asymptomatic (latent TB) and non-contagious. However, approximately 10% of latent TB cases may advance to active TB (active or symptomatic TB). Some usual symptoms of active TB comprise continuing chronic cough, hemoptysis, night sweating, and weight loss. Active TB is associated with a high mortality rate if left untreated. The 2021 TB report of the World Health Organization (WHO) states that TB is one of the top 10 reasons for global deaths, about one-quarter of the global population is affected by Mtb, and the global burden of TB is expected to increase due to the COVID-19 pandemic.

tuberculosis drug-resistance Mmpl3 SQ109 clinical studies patent

1. Mycobacterial Membrane Protein Large 3 (MmpL3)

MmpL is a transport protein (trehalose monomycolate flippase) in Mtb. There are about 13 MmpLs, but only MmpL3 is essential in Mtb [1]. The physiological role, structure, and properties of MmpL3 are well described in the literature [1][2][3][4][5][6]. Mycolic acid (MA) is an essential component of the MA-based hydrophobic outer cell wall of Mtb [1][2][3][4][5][6]. MA is produced in the cytoplasm of the Mtb cell. In the cytoplasm of the Mtb, the type I polyketide synthase 13 (Pks13) drives the interaction of MA and trehalose to produce trehalose monomycolate (TMM). MmpL3 is located at the plasma membrane of the Mtb. MmpL3 is responsible for transporting TMM from the cytoplasm to the inner membrane of the Mtb. In the inner membrane, Ag85 mediates the conversion of TMM to trehalose dimycolate (TDM) and trehalose. The trehalose returns to the cytoplasm via the SugABC-Lpqy transporter to restart this cycle. The TDM makes the covalent bond with the arabinogalactan polysaccharides to synthesize a packed and MA-based hydrophobic outer cell wall of Mtb (Figure 1).
Figure 1. Mechanism of action of MmpL3 inhibitor (SQ109).
The MA-based hydrophobic outer cell wall of Mtb is impermeable to many chemical compounds, including antibiotics, and protects and contributes to the pathogenic success of Mtb [1][3]. Therefore, the expression of MmpL3 is essential for Mtb’s survival and pathogenicity [1][2][3][4][5][6]. The inhibitors of MmpL3 (SQ109) cause the diminution of MmpL3, which leads to the cessation of cell wall synthesis, cell division, and thevrapid death of Mtb [1][2][3][4][5][6].

2. Literature on MmpL3 Inhibitors

The literature on MmpL3 inhibitors was searched on the PubMed database using “MmpL3” as a keyword on 1 October 2022. Herein, 146 articles were provided, including 21 review articles. The summary of 12 relevant and recent review articles is mentioned in Table 1. The authors did not find an MmpL3 inhibitor-based review article discussing clinical studies on MmpL3 inhibitors (SQ109), the development of SQ109, or the patent literature of MmpL3. This aspect provides novelty to the current review article over the previously published reviews on MmpL3 inhibitors.
Table 1. Summary of relevant and recent review articles on MmpL3.

3. Clinical Studies on MmpL3 Inhibitors

Studies [1][3][6][7][10][11][12][13][14][15][16] have disclosed the chemistry of some important inhibitors of MmpL3 (SQ109, NITD-304, NITD-349, AU1235, CRS400393, BM212, THPP, spiropiperidine, TBL-140, ICA38, HC2091, BM533, BM635, rimonabant, C215, and PIPD1). The clinical studies on MmpL3 inhibitors were searched on 1 October 2022, on the clinicaltrial.gov database [17] utilizing different keywords (SQ109 = 7 studies; No anti-TB study found for NITD-304, NITD-349, AU1235, CRS400393, BM212, THPP, spiropiperidine, TBL-140, ICA38, HC2091, BM533, BM635, rimonabant, C215, or PIPD1). A general search on PubMed was also conducted with the earlier mentioned keywords in the clinical trial and randomized controlled trial section of PubMed. Three studies were identified for the “SQ109” keyword [18][19][20], while other keywords did not produce clinical studies related to TB. The summary of clinical studies on SQ109 is provided in the SQ109 section herein.

4. SQ109

SQ109 (Synonym: NSC722041; Molecular Formula: C22H38N2; Molecular Weight: 330.55; CAS registry number: 502487-67-4; ChemSpider ID: 4438718; PubChem substance ID: 175426955; PubChem CID: 5274428; Figure 2) is a 1,2-ethylenediamine-based analog of EMB (Figure 2) [21][22]. The 1,2-ethylenediamine linker is essential for the anti-TB activity of SQ109 and EMB [23].
Figure 2. Chemical structures of SQ109 and ethambutol.
Infectex and Sequella are developing SQ109 in partnership to treat MDR pulmonary TB [24][25]. SQ109 was developed by focusing on EMB, but they share an uncommon chemical skeleton (Figure 2) and mechanism of action. The chemical structure, synthesis, anti-TB activity, oral bioavailability, and acid stability of SQ109 were first disclosed in 2003 [21][26]. The development timeline of SQ109 is presented in Figure 3.
Figure 3. The development timeline of SQ109.

4.1. Mechanism of Action

SQ109 demonstrates its anti-TB activity through three different mechanisms comprising inhibition of MmpL3 (Figure 1), biosynthesis of quinones (MenG and MenA), and a reduction in ATP synthesis in Mtb [24][25][26][27].

4.2. Preclinical Studies

The preclinical studies have established the efficacy of SQ109 against all forms of TB, including DS-TB, DR-TB, and the slow vegetative form of Mtb (latent-TB) [25][26] (Table 2). SQ109 has also shown activity against Aspergillus fumigatus, Candida spp., Helicobacter pylori, Haemophilus influenzae, and Streptococcus pneumoniae [25]. SQ109 presented low oral bioavailability but achieved 45-fold higher concentrations in TB murine target organs (lung and spleen) than in plasma, reduced TB-treatment time by about 25–30% in in vivo models, and exhibited synergistic effects with INH, RIF, CFZ, and BDQ [24][25][26] (Table 2).
Table 2. The anti-TB activity of SQ109 and its combinations against Mtb.

4.3. Clinical Studies on SQ109

The clinical studies on SQ109 were searched on the clinicaltrial.gov database [17] and PubMed. The summary of clinical studies on SQ109 is provided in Table 3.
Table 3. Summary of clinical studies on SQ109.

References

  1. Bolla, J.R. Targeting MmpL3 for anti-tuberculosis drug development. Biochem. Soc. Trans. 2020, 48, 1463–1472.
  2. Su, C.-C.; Klenotic, P.A.; Bolla, J.R.; Purdy, G.E.; Robinson, C.V.; Yu, E.W. MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine. Proc. Natl. Acad. Sci. USA 2019, 116, 11241–11246.
  3. Umare, M.D.; Khedekar, P.B.; Chikhale, R.V. Mycobacterial Membrane Protein Large 3 (MmpL3) Inhibitors: A Promising Approach to Combat Tuberculosis. Chem. Med. Chem. 2021, 16, 3136–3148.
  4. Belardinelli, J.M.; Yazidi, A.; Yang, L.; Fabre, L.; Li, W.; Jacques, B.; Angala, S.K.; Rouiller, I.; Zgurskaya, H.I.; Sygusch, J.; et al. Structure-function profile of MmpL3, the essential mycolic acid transporter from Mycobacterium tuberculosis. ACS Infect. Dis. 2016, 2, 702–713.
  5. Su, C.-C.; Klenotic, P.A.; Cui, M.; Lyu, M.; Morgan, C.E.; Yu, E.W. Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport. PLoS Biol. 2021, 19, e3001370.
  6. Xu, Z.; Meshcheryakov, V.A.; Poce, G.; Chng, S.-S. MmpL3 is the flippase for mycolic acids in mycobacteria. Proc. Natl. Acad. Sci. USA 2017, 114, 7993–7998.
  7. Bajad, N.G.; Singh, S.K.; Singh, S.K.; Singh, T.D.; Singh, M. Indole: A promising scaffold for the discovery and development of potential anti-tubercular agents. Curr. Res. Pharmacol. Drug Discov. 2022, 3, 100119.
  8. Addison, W.; Frederickson, M.; Coyne, A.G.; Abell, C. Potential therapeutic targets from Mycobacterium abscessus (Mab): Recently reported efforts towards the discovery of novel antibacterial agents to treat Mab infections. RSC Med. Chem. 2022, 13, 392–404.
  9. Black, T.A.; Buchwald, U.K. The pipeline of new molecules and regimens against drug-resistant tuberculosis. J. Clin. Tuberc. Other Mycobact. Dis. 2021, 25, 100285.
  10. Sethiya, J.P.; Sowards, M.A.; Jackson, M.; North, E.J. MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections. Int. J. Mol. Sci. 2020, 21, 6202.
  11. Shao, M.; McNeil, M.; Cook, G.M.; Lu, X. MmpL3 inhibitors as antituberculosis drugs. Eur. J. Med. Chem. 2020, 200, 112390.
  12. Dey, R.; Nandi, S.; Samadder, A.; Saxena, A.; Saxena, A.K. Exploring the potential inhibition of candidate drug molecules for clinical investigation based on their docking or crystallographic analyses against M. tuberculosis enzyme targets. Curr. Top. Med. Chem. 2020, 20, 2662–2680.
  13. Goldman, R.C. Target Discovery for New Antitubercular Drugs Using a Large Dataset of Growth Inhibitors from PubChem. Infect. Disord. Drug Targets 2020, 20, 352–366.
  14. Saxena, A.K.; Singh, A. Mycobacterial tuberculosis Enzyme Targets and their Inhibitors. Curr. Top. Med. Chem. 2019, 19, 337–355.
  15. Campaniço, A.; Moreira, R.; Lopes, F. Drug discovery in tuberculosis. New drug targets and antimycobacterial agents. Eur. J. Med. Chem. 2018, 150, 525–545.
  16. Rayasam, G.V. MmpL3 a potential new target for development of novel anti-tuberculosis drugs. Expert Opin. Ther. Targets 2014, 18, 247–256.
  17. NIH. Available online: https://clinicaltrials.gov/ (accessed on 1 October 2022).
  18. Heinrich, N.; Dawson, R.; du Bois, J.; Narunsky, K.; Horwith, G.; Phipps, A.J.; Nacy, C.A.; Aarnoutse, R.E.; Boeree, M.J.; Gil-lespie, S.H.; et al. Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA); Pan African Consortium for the Evaluation of Antituberculosis Antibiotics PanACEA. Early phase evaluation of SQ109 alone and in combination with rifampicin in pulmonary TB patients. J. Antimicrob. Chemother. 2015, 70, 1558–1566.
  19. Boeree, M.J.; Heinrich, N.; Aarnoutse, R.; Diacon, A.H.; Dawson, R.; Rehal, S.; Kibiki, G.S.; Churchyard, G.; Sanne, I.; E Ntinginya, N.; et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: A multi-arm, multi-stage randomised controlled trial. Lancet Infect. Dis. 2016, 17, 39–49.
  20. Kayigire, X.A.; Friedrich, S.O.; van der Merwe, L.; Donald, P.R.; Diacon, A.H. Simultaneous staining of sputum smears for acid-fast and lipid-containing Myobacterium tuberculosis can enhance the clinical evaluation of antituberculosis treatments. Tuberculosis 2015, 95, 770–779.
  21. Lee, R.E.; Protopopova, M.; Crooks, E.; Slayden, R.A.; Terrot, M.; Barry, C.E., 3rd. Combinatorial Lead Optimization of -Diamines Based on Ethambutol as Potential Antituberculosis Preclinical Candidates. J. Comb. Chem. 2003, 5, 172–187.
  22. Protopopova, M.; Hanrahan, C.; Nikonenko, B.; Samala, R.; Chen, P.; Gearhart, J.; Einck, L.; Nacy, C.A. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J. Antimicrob. Chemother. 2005, 56, 968–974.
  23. Bahuguna, A.; Rawat, D.S. An overview of new antitubercular drugs, drug candidates, and their targets. Med. Res. Rev. 2020, 40, 263–292.
  24. SQ109. Available online: https://infectex.ru/en/products/sq-109/ (accessed on 1 October 2022).
  25. Sacksteder, K.A.; Protopopova, M.; Barry, C.E., 3rd; Andries, K.; Nacy, C.A. Discovery and development of SQ109: A new an-titubercular drug with a novel mechanism of action. Future Microbiol. 2012, 7, 823–837.
  26. SQ109. Tuberculosis (Edinb) 2008, 88, 159–161.
  27. Iqbal, I.; Bajeli, S.; Akela, A.; Kumar, A. Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery. Pathogens 2018, 7, 24.
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