Cephamycins inhibit pathogen sporulation and effectively treat recurrent Clostridioides difficile infection

Yogitha N. Srikhanta, Melanie L. Hutton, Milena M. Awad, Nyssa Drinkwater, Julie Singleton, Sophie L. Day, Bliss A. Cunningham, Sheena McGowan, Dena Lyras

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Spore-forming bacteria encompass a diverse range of genera and species, including important human and animal pathogens, and food contaminants. Clostridioides difficile is one such bacterium and is a global health threat because it is the leading cause of antibiotic-associated diarrhoea in hospitals. A crucial mediator of C. difficile disease initiation, dissemination and re-infection is the formation of spores that are resistant to current therapeutics, which do not target sporulation. Here, we show that cephamycin antibiotics inhibit C. difficile sporulation by targeting spore-specific penicillin-binding proteins. Using a mouse disease model, we show that combined treatment with the current standard-of-care antibiotic, vancomycin, and a cephamycin prevents disease recurrence. Cephamycins were found to have broad applicability as an anti-sporulation strategy, as they inhibited sporulation in other spore-forming pathogens, including the food contaminant Bacillus cereus. This study could directly and immediately affect treatment of C. difficile infection and advance drug development to control other important spore-forming bacteria that are problematic in the food industry (B. cereus), are potential bioterrorism agents (Bacillus anthracis) and cause other animal and human infections.

Original languageEnglish
Number of pages9
JournalNature Microbiology
DOIs
Publication statusAccepted/In press - 12 Aug 2019

Keywords

  • antibiotics
  • bacterial pathogenesis
  • bacterial physiology
  • clostridium difficile

Cite this

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title = "Cephamycins inhibit pathogen sporulation and effectively treat recurrent Clostridioides difficile infection",
abstract = "Spore-forming bacteria encompass a diverse range of genera and species, including important human and animal pathogens, and food contaminants. Clostridioides difficile is one such bacterium and is a global health threat because it is the leading cause of antibiotic-associated diarrhoea in hospitals. A crucial mediator of C. difficile disease initiation, dissemination and re-infection is the formation of spores that are resistant to current therapeutics, which do not target sporulation. Here, we show that cephamycin antibiotics inhibit C. difficile sporulation by targeting spore-specific penicillin-binding proteins. Using a mouse disease model, we show that combined treatment with the current standard-of-care antibiotic, vancomycin, and a cephamycin prevents disease recurrence. Cephamycins were found to have broad applicability as an anti-sporulation strategy, as they inhibited sporulation in other spore-forming pathogens, including the food contaminant Bacillus cereus. This study could directly and immediately affect treatment of C. difficile infection and advance drug development to control other important spore-forming bacteria that are problematic in the food industry (B. cereus), are potential bioterrorism agents (Bacillus anthracis) and cause other animal and human infections.",
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Cephamycins inhibit pathogen sporulation and effectively treat recurrent Clostridioides difficile infection. / Srikhanta, Yogitha N.; Hutton, Melanie L.; Awad, Milena M.; Drinkwater, Nyssa; Singleton, Julie; Day, Sophie L.; Cunningham, Bliss A.; McGowan, Sheena; Lyras, Dena.

In: Nature Microbiology, 12.08.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Awad, Milena M.

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AU - Singleton, Julie

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AU - Lyras, Dena

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