[SCAN] Molecular and cell biology of carbapenem resistance in the human pathogen Clostridioides difficile

Title: Molecular and cell biology of carbapenem resistance in the human pathogen Clostridioides difficile

Speaker: Adriano O. Henriques, Head of Microbial Development

Abstract: The intense use and misuse of antibiotics, and their inappropriate disposal, have led to a worldwide rise in the pervasiveness of antibiotic-resistant bacteria, strongly curtailing our ability to treat bacterial infections in both humans and animals. A striking example comes from Clostridioides difficile (CDIFF), the leading causative agent of a range of intestinal diseases linked to antibiotic therapy with symptoms ranging from mild diarrhea to life-threatening conditions such as pseudomembranous colitis, bowel perforation and sepsis. CDIFF is a major pathogen causing close to 500,000 infections and 29,000 deaths per year in the United States, while 125.00 cases and 3.700 deaths are registered yearly in Europe. Up to 30% of the cases of C. difficile infection (or CDI) result in disease relapse, often followed by subsequent episodes. Relapse makes a major contribution to the annual economic burden of CDI, estimated at over US$ 1 billion in the US and €3 billion in Europe. Although a major nosocomial pathogen, the intensification in community-associated CDI, together with the risk of zoonotic transmission, justifies the label of “urgent threat” by the Centers for Disease Control and Prevention. Dysbiosis linked to antibiotic therapy allows ingested CDIFF spores to germinate in the intestine and to colonize the colon. Since most epidemic strains are multi-resistant, growth is maintained even during antibiotic therapy.

The fluoroquinolones were one of the most frequently prescribed antibiotic classes during the late 1990s and early 2000s and heavily used as the main therapy against infections by Gram (-) bacteria in hospitals. This created the selective pressure for the acquisition and maintenance of a fluoroquinolone-resistance mutation in gyrA that lead to the emergence and spreading of epidemic clones that caused, and still cause, severe disease outbreaks worldwide. At present, b-lactams of the carbapenem class have replaced the fluoroquinolones. Not surprisingly, carbapenem-resistant CDIFF strains have emerged and are highly disseminated in some countries, recapitulating the events of two decades ago.

The selective pressure that carbapenem therapy imposes upon CDIFF will eventually lead to the spread of these strains worldwide. The spreading of IMP-resistant CDIFF would be catastrophic, and the lack of knowledge on the paths and molecular mechanisms by which resistance emerges puts us in a vulnerable position. The group has addressed this question. We discuss our current knowledge of the molecular and cellular mechanisms underlying carbapenem resistance in CDIFFF.

ITQB NOVA Virtual Auditorium
https://zoom.us/j/729768442