Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.
Freimann Life Sciences Center, University of Notre Dame, Notre Dame, IN 46556.
Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2304110120. doi: 10.1073/pnas.2304110120. Epub 2023 May 8.
infection (CDI) is the most lethal of the five CDC urgent public health treats, resulting in 12,800 annual deaths in the United States alone [ (2019), www.cdc.gov/DrugResistance/Biggest-Threats.html]. The high recurrence rate and the inability of antibiotics to treat such infections mandate discovery of new therapeutics. A major challenge with CDI is the production of spores, leading to multiple recurrences of infection in 25% of patients [C. P. Kelly, J. T. LaMont, , 1932-1940 (2008)], with potentially lethal consequence. Herein, we describe the discovery of an oxadiazole as a bactericidal anti- agent that inhibits both cell-wall peptidoglycan biosynthesis and spore germination. We document that the oxadiazole binds to the lytic transglycosylase SleC and the pseudoprotease CspC for prevention of spore germination. SleC degrades the cortex peptidoglycan, a critical step in the initiation of spore germination. CspC senses germinants and cogerminants. Binding to SleC is with higher affinity than that to CspC. Prevention of spore germination breaks the nefarious cycles of CDI recurrence in the face of the antibiotic challenge, which is a primary cause of therapeutic failure. The oxadiazole exhibits efficacy in a mouse model of recurrent CDI and holds promise in clinical treatment of CDI.
感染（CDI）是美国五种最致命的 CDC 紧急公共卫生问题之一，仅在美国每年就有 12800 人因此死亡[（2019 年），www.cdc.gov/DrugResistance/Biggest-Threats.html]。高复发率和抗生素无法治疗此类感染，这就要求开发新的疗法。CDI 的一个主要挑战是孢子的产生，导致 25%的患者反复感染[C. P. Kelly，J. T. LaMont，，1932-1940（2008）]，可能导致致命后果。在此，我们描述了一种恶二唑作为杀菌剂的发现，它可以抑制细胞壁肽聚糖的生物合成和孢子萌发。我们证明恶二唑与溶菌酶 SleC 和假蛋白酶 CspC 结合，以防止孢子萌发。SleC 降解皮层肽聚糖，这是孢子萌发起始的关键步骤。CspC 感知发芽剂和共发芽剂。与 SleC 的结合亲和力高于与 CspC 的结合亲和力。阻止孢子萌发可以打破抗生素挑战下 CDI 复发的恶性循环，这是治疗失败的主要原因。恶二唑在复发性 CDI 的小鼠模型中表现出疗效，并有望在 CDI 的临床治疗中得到应用。
