Biological Evaluation Of Membrane-active Compounds As Treatment For Clostridium Difficile Infection
Clostridium difficile infection (CDI), which is caused by a spore-forming, gram-positive anaerobe, named C. difficile, is the leading cause of the hospital-acquired antibiotic-associated diarrhea. Hospitalized elderly patients, who receive broad-spectrum antibiotics, are mostly affected. However, recent clinical observations demonstrate that the incidence of CDI is also increasing in the community and occurs without previously established risk factors. With the recent emergence of epidemic strains of C. difficile, such as BI/NAP1/027, the severity of the CDI has increased in the North America, as well as in other parts of the world. The US Centers for Disease Control and Prevention (CDC), in their 2013-threat report, has categorized C. difficile as an urgent threat pathogen. In 2011, C. difficile caused 29,000 deaths in the United States alone. Despite the increase of incidence and the severity of the disease, the treatment options for CDI are limited. Metronidazole and vancomycin have been the first line treatment for the last three decades, and recently, in 2011, the FDA approved fidaxomicin for the treatment of CDI. The pathogenesis of C. difficile relies on the production of toxins (A and B), and sporulation that primarily occurs in late logarithmic and stationary-phase cells. These cell types are characteristically resistant to antibiotics. We hypothesize that since vancomycin and metronidazole are less effective against slow-growing cells; this hampers their efficacy. Conversely, compounds targeting the bacterial membrane may have superior efficacy by retaining potent activity against growing and non-growing cells. Metronidazole is also further hampered by its poor pharmacokinetics. This thesis, therefore, examined the properties of the membrane-active compound, surotomycin on C. difficile (Chapter 2 and chapter 3).Surotomycin, also known as CB-183,315, is an orally active lipopeptide and in the phase 3 clinical trials for the treatment of CDI. Although, in vivo, this compound demonstrated better clinical efficacy in CDI, compared to other commonly used drugs, and caused membrane potential disruption in S. aureus, its action is not well characterized in C. difficile. Therefore, this study, using in vitro assays, provide validation of surotomycin’s action and effects on virulence. In addition, as a part of a collaborative team, this study has evaluated the gastrointestinal pharmacokinetics and the in vivo efficacies of novel hybrid compounds, MTZ-TA, using hamster model of CDI (Chapter 4).