Virtual ACG 2020

Pinion, Sheila

doi:10.1016/s2468-1253(20)30368-x

Cited by 1 publication

(1 citation statement)

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“…The failure was attributed to the low dose used and to inclusion based on diagnosis by PCR assay rather than the presence of C. difficile toxin in feces ( 27 ). A phase III clinical trial with SER-109 recently showed that 11.1% in the SER-109 group had CDI recurrence compared to 41.3% in the placebo control, with 88.9% of patients in the SER-109 group had a sustained clinical response relative to 58.7% in the placebo group ( 28 ). Another report is the use of the monoclonal antibody bezlotoxumab against TcdB, which reduces recurrence by 10% when administered with an antibiotic ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination

Janardhanan

Kim

Qian

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%