SQ109 is a novel, ampicillin-type, Mycobacterium tuberculosis cell wall synthesis inhibitor that effectively inhibits the growth of Mycobacterium tuberculosis (Mtb) by interfering with the biosynthesis of mycolic acid and other cell wall components[1, 2]. SQ109 is a synthetic, small-molecule, diamine-type anti-tuberculosis drug that targets and inhibits Mycobacterium membrane protein L3 (MmpL3), making it useful for treating drug-resistant tuberculosis[3]. SQ109 effectively inhibits the growth of the parasitic protozoan Trypanosoma brucei, killing the cells with an IC50 value of 50±8nM[4].
In vitro, treatment of Leishmania donovani-infected macrophages with SQ109 (0-10μM) for 48h inhibited the proliferation of L. donovani parasites in a dose-dependent manner[5]. Treatment of M. tuberculosis with SQ109 (10, 20μM) for 5 and 10 days, respectively, reduced the bacterial colony count by 1 and 2 log10 units[6].
In vivo, intraperitoneal injection of SQ109 (30, 100mg/kg/day) for 5 days in mice infected with Leishmania parasites significantly reduced the parasite burden in the blood and prolonged mouse survival; however, the parasite burden in the blood increased rapidly after treatment cessation[7].
References:
[1] Tahlan K, Wilson R, Kastrinsky D B, et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis[J]. Antimicrobial agents and chemotherapy, 2012, 56(4): 1797-1809.
[2] Sacksteder K A, Protopopova M, Barry C E, et al. Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action[J]. Future microbiology, 2012, 7(7): 823-837.
[3] Li K, Schurig-Briccio L A, Feng X, et al. Multitarget drug discovery for tuberculosis and other infectious diseases[J]. Journal of medicinal chemistry, 2014, 57(7): 3126-3139.
[4] Veiga-Santos P, Li K, Lameira L, et al. SQ109, a new drug lead for Chagas disease[J]. Antimicrobial agents and chemotherapy, 2015, 59(4): 1950-1961.
[5] Gil Z, Martinez-Sotillo N, Pinto-Martinez A, et al. SQ109 inhibits proliferation of Leishmania donovani by disruption of intracellular Ca2+ homeostasis, collapsing the mitochondrial electrochemical potential (Δ Ψ m) and affecting acidocalcisomes[J]. Parasitology research, 2020, 119(2): 649-657.
[6] Zheng H, Williams J T, Coulson G B, et al. HC2091 kills Mycobacterium tuberculosis by targeting the MmpL3 mycolic acid transporter[J]. Antimicrobial agents and chemotherapy, 2018, 62(7): 10.1128/aac. 02459-17.
[7] Baek K H, Phan T N, Malwal S R, et al. In vivo efficacy of SQ109 against Leishmania donovani, Trypanosoma spp. and Toxoplasma gondii and in vitro activity of SQ109 metabolites[J]. Biomedicines, 2022, 10(3): 670.