A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination.
Jeshina JanardhananChoon KimYuanyuan QianJingdong YangJayda E MeiselDerong DingEnrico SperiValerie A SchroederWilliam R WolterAllen G OliverShahriar MobasheryMayland ChangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Clostridioides difficile 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 [ Antibiotic Resistance Threats in the United States, 2019 (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, N. Engl. J. Med. 359 , 1932-1940 (2008)], with potentially lethal consequence. Herein, we describe the discovery of an oxadiazole as a bactericidal anti- C. difficile 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.
Keyphrases
- cell wall
- bacillus subtilis
- clostridium difficile
- public health
- small molecule
- mouse model
- plant growth
- end stage renal disease
- newly diagnosed
- induced apoptosis
- ejection fraction
- high throughput
- cell cycle
- prognostic factors
- oxidative stress
- mass spectrometry
- functional connectivity
- cell cycle arrest
- patient reported outcomes
- cell proliferation
- cell death
- arabidopsis thaliana
- big data