Molecular mechanisms of metronidazole resistance in Bacteroides fragilis

• Applicant: Professorin Dr. Meina Neumann-Schaal
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574052932

Bacteroides fragilis is an abundant human gut commensal but can also cause severe disease when it perforates the intestinal wall and reaches other body sites. B. fragilis infections are treated with several antimicrobials including the 5-nitroimidazole drug metronidazole, but antimicrobial resistance can pose serious problems. The overall occurrence of metronidazole resistance in B. fragilis is still low but in some countries higher rates have been reported. Metronidazole resistance is a complex phenomenon which involves changes in the cellular metabolism. When metronidazole resistance is induced in the laboratory, intracellular iron levels are decreased leading to the loss of numerous iron-dependent enzyme activities. In resistant clinical isolates this does not seem to be the case but the central carbon metabolism in these strains has not been studied so far. Most but not all resistant clinical isolates encode Nim proteins which greatly facilitate the development of metronidazole resistance. Recent research showed that Nim proteins have far reaching effects on the cellular physiology by modifying the antioxidant defense and induce the expression of flavoprotein A (FprA). Nim proteins also enable resistance development in laboratory strains without negatively affecting intracellular iron levels. We hypothesize that resistance in clinical isolates is associated with metabolic changes and that sublethal metronidazole levels prime the metabolism for better adaptation to metronidazole. We further hypothesize that cytochrome ubiquinol oxidase (CydA) can reduce and thereby activate metronidazole and that Nim proteins inhibit CydA. This necessitates the previously described upregulation of FprA which has the same role as CydA, i.e. the reduction of molecular oxygen to water. Finally, we will use anti-FprA antibodies to screen a selection of clinical isolates. We hypothesize that expression of FprA is positively correlated with clinical resistance.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Dr. David Leitsch