[R01] Clostridiodes difficile spore germination and therapeutic intervention

Ente: National Institute of Allergy and Infectious Diseases

Scadenza: 2031-04-30

Importo max: 769.354 EUR

Paese: US

Descrizione

Abstract Infections caused by Clostridioides difficile (previously known as Clostridium difficile) are urgent threats resulting in more than 7-fold deaths in the United States than the other four urgent bacterial threats combined. The normal gut flora prevents colonization by C. difficile. However, usage of broad-spectrum antibiotics disrupts the gut microflora, allowing for C. difficile colonization. C. difficile spores germinate in the presence of host bile acids to vegetative cells, which produce toxins that damage gut mucosa, promoting inflammation and diarrhea. The vegetative cells produce more spores that are either shed/eliminated in feces or germinate to vegetative cells to start another cycle of infection. About 25% of patients have recurrent C. difficile infection. Spores can remain dormant for months and are not affected by antibiotics. Understanding spore germination is key to halting recurrent infections, which are the cause of significant morbidity and mortality. There are no antibiotics in the clinic or in development that inhibit spore germination. We have discovered a class of antibiotics called the oxadiazoles that kill C. difficile vegetative cells and inhibit spore germination. We showed that the target in spores is SleC, a lytic transglycosylase that turns over the spore cell wall for the onset of spore germination. We propose to elucidate the machinery of spore germination in Specific Aim 1, which will be the target of inhibition for prevention of spore germination. In addition, we propose in Specific Aim 2 a lead-optimization plan for the oxadiazoles for the discovery of pre-clinical candidates of spore germination inhibitors with improved attributes that include desirable safety profile, pharmacokinetic properties, in vitro activity, selectivity, and efficacy. Istituzione: UNIVERSITY OF NOTRE DAME PI: Mayland F Chang Progetto: 1R01AI198244-01

Settori: National Institute of Allergy and Infectious Diseases

Vai al bando originale

Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.