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.
SQ109是一种新型的氨苄青霉素结核杆菌细胞壁合成抑制剂，能够通过干扰分枝杆菌酸和细胞壁其他组分的生物合成，有效抑制结核分枝杆菌（Mtb）的生长[1, 2]。SQ109是一种合成的小分子二胺类抗结核药物，能够靶向抑制分枝杆菌膜蛋白大3（MmpL3），用于治疗耐药结核病[3]。SQ109能够有效抑制寄生虫的锥虫成虫期，杀死细胞，IC50值为50±8nM[4]。
在体外，SQ109（0-10μM）处理感染了利什曼原虫（L. donovani）寄生虫的巨噬细胞48h，以剂量依赖性方式抑制了L. donovani幼虫的增殖[5]。SQ109（10, 20μM）处理结核分枝杆菌5天和10天，分别使菌落数降低了1个和2个对数[6]。
在体内，SQ109（30, 100mg/kg/day）通过腹腔注射治疗寄生虫血症小鼠5天，显著抑制了小鼠血液中的寄生虫负荷，延长了小鼠的存活时间，但是停药后血液中的寄生虫负荷迅速增加[7]。