Trivedi Keya, LaRock Christopher N
Department of Biology, Emory University, Atlanta, Georgia, USA.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
Microbiol Spectr. 2025 Aug 5;13(8):e0075825. doi: 10.1128/spectrum.00758-25. Epub 2025 Jun 23.
The obligate human pathogen (also known as GAS; Group A ) carries high morbidity and mortality, primarily in impoverished or resource-poor regions. The failure rate of monotherapy with conventional antibiotics is high, and invasive infections by this bacterium frequently require extensive supportive care and surgical intervention. Thus, it is important to find new compounds with adjunctive therapeutic benefits. The conserved secreted protease streptopain (Streptococcal pyogenic exotoxin B; SpeB) directly contributes to disease pathogenesis by inducing pathological inflammation, degrading tissue, and promoting the evasion of antimicrobial host defense proteins. This study screened 400 diverse off-patent drugs and drug-like compounds for inhibitors of streptopain proteolysis. Lead compounds were tested for activity at lower concentrations and anti-virulence activities during infection. Significant inhibition of streptopain was seen for pentamidine, an anti-protozoal drug approved for the treatment of Pneumocystis pneumonia, leishmaniasis, and trypanosomiasis. Streptopain inhibition rendered GAS susceptible to killing by human innate immune cells. These studies identify unexploited molecules as new starting points for drug discovery and a potential for repurposing existing drugs for the treatment of infections by GAS.IMPORTANCE is a common cause of severe invasive infections. Repeated infections can trigger autoimmune diseases such as acute rheumatic fever and rheumatic heart disease. This study examines how targeting a specific, highly conserved virulence factor of the secreted cysteine protease streptopain can sensitize a serious pathogen to killing by the immune system. Manipulating the host-pathogen interaction, rather than attempting to directly kill a microbe, is a promising therapeutic strategy. Notably, its benefits include limiting off-target effects on the microbiota. Streptopain inhibitors, including the antifungal and antiparasitic drug pentamidine as identified in this work, may therefore be useful in the treatment of infection.
专性人类病原体（也称为A群链球菌；GAS）具有高发病率和死亡率，主要发生在贫困或资源匮乏地区。传统抗生素单药治疗的失败率很高，这种细菌引起的侵袭性感染通常需要广泛的支持治疗和手术干预。因此，寻找具有辅助治疗益处的新化合物很重要。保守的分泌型蛋白酶链激酶（化脓性链球菌外毒素B；SpeB）通过诱导病理性炎症、降解组织和促进逃避抗菌宿主防御蛋白，直接导致疾病发病机制。本研究筛选了400种不同的非专利药物和类药物化合物，以寻找链激酶蛋白水解的抑制剂。对先导化合物进行了较低浓度下的活性测试以及感染期间的抗毒力活性测试。已批准用于治疗肺孢子菌肺炎、利什曼病和锥虫病的抗寄生虫药物喷他脒对链激酶有显著抑制作用。链激酶抑制使A群链球菌易被人类先天免疫细胞杀死。这些研究确定了未被开发的分子作为药物发现的新起点，以及将现有药物重新用于治疗A群链球菌感染的潜力。重要性A群链球菌是严重侵袭性感染的常见原因。反复感染可引发自身免疫性疾病，如急性风湿热和风湿性心脏病。本研究探讨了靶向分泌型半胱氨酸蛋白酶链激酶的一种特定、高度保守的毒力因子如何使一种严重病原体对免疫系统的杀伤敏感。操纵宿主-病原体相互作用，而不是试图直接杀死微生物，是一种有前景的治疗策略。值得注意的是，其益处包括限制对微生物群的脱靶效应。因此，包括本研究中鉴定的抗真菌和抗寄生虫药物喷他脒在内的链激酶抑制剂可能有助于治疗A群链球菌感染。
