Combatting Clostridioides difficile: stress, adaptation and antimicrobial resistance

Abstract

Clostridioides difficile is a Gram-positive gut pathogen capable of causing disease resulting in (mild) diarrhea associated with mild- or severe inflammation of the gut. Patients that have been recently treated with antibiotics, have comorbidities, or the elderly, are most susceptible to developing a C. difficile infection (CDI). Despite this, antibiotic use is the first line therapy for CDI treatment. The antibiotics used in CDI treatment are metronidazol, vancomycin or fidaxomicin. CDI can be difficult to treat and can recur, in which case a fecal microbiota transplantation (FMT) can resolve infection.

C. difficile is intrinsically resistant to many different antibiotics. For this reason it is important to find and develop novel antibiotics and treatments for CDI. However, bacteria are capable of adapting to unfavorable environments (such as the presence of antibiotics) and it is crucial to understand how these adaptive processes are regulated. This thesis describes how low concentrations of a novel, experimental antibiotic, ibezapolstat, produces secondary effects that can facilitate C. difficile’s adaptive response. Part of this adaptation is mediated by the general stress response, which is characterized in this thesis. Additionally, this thesis describes two novel ways in which C. difficile can become resistant to metronidazole.