Malwal Satish R, Garcia-Rubio Rocio, Kordalewska Milena, Patterson Hoja, Zhang Chi, Calderin Jorge D, Zhou Ruijie, Pandey Akanksha M, Shor Erika, Perlin David S, Wiederhold Nathan P, Ostrosky-Zeichner Luis, Fratti Rutilio, Nacy Carol, Oldfield Eric
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
ACS Infect Dis. 2025 Jun 13;11(6):1662-1672. doi: 10.1021/acsinfecdis.5c00210. Epub 2025 May 14.
We investigated the activity of the tuberculosis drug SQ109 against 16 fungal pathogens: , , , , , , , , , , spp., spp., spp., spp., and . MIC values varied widely (125 ng/mL to >64 μg/mL) but in many cases we found promising (MIC ∼ 4 μg/mL) activity as well as MFC/MIC ratios of ∼ 2. SQ109 metabolites were inactive. The activity of 12 analogs of SQ109 against correlated with protonophore uncoupling activity, suggesting mitochondrial targeting, consistent with the observation that growth inhibition was rescued by agents which inhibit ROS species accumulation. SQ109 disrupted H/Ca homeostasis in vacuoles, and there was synergy (FICI ∼ 0.26) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multitarget activity.
我们研究了抗结核药物SQ109对16种真菌病原体的活性： 、 、 、 、 、 、 、 、 、 、 属、 属、 属、 属、 以及 。最低抑菌浓度（MIC）值差异很大（125纳克/毫升至>64微克/毫升），但在许多情况下，我们发现其具有有前景的活性（MIC约为4微克/毫升）以及约为2的最低杀菌浓度（MFC）/最低抑菌浓度（MIC）比值。SQ109的代谢产物无活性。SQ109的12种类似物对 的活性与质子载体解偶联活性相关，表明其作用于线粒体，这与生长抑制可被抑制活性氧物质积累的药物挽救的观察结果一致。SQ109破坏了 液泡中的H/Ca稳态，并且与匹伐他汀存在协同作用（联合抑菌系数约为0.26），表明其参与了类异戊二烯生物合成途径的抑制。因此，SQ109是一种具有多靶点活性的潜在抗真菌剂。
