Pyruvate:ferredoxin oxidoreductase and Ferredoxin system (PFOR/Fd system)

The Pyruvate:ferredoxin oxidoreductase (PFOR) and Ferredoxin system is the primary metabolic pathway responsible for the reductive activation of nitroimidazole antibiotics, such as metronidazole, in anaerobic bacteria and protozoa (Müller, 1986, PMID: 3521636). These components, often localized in specialized organelles like hydrogenosomes, normally function in anaerobic energy metabolism by transferring low-potential electrons from the oxidation of pyruvate to ferredoxin (Land & Johnson, 1999, PMID: 10506454). In the presence of metronidazole, ferredoxin acts as a high-energy electron donor that reduces the drug's nitro group, creating short-lived, highly reactive nitro radical anions (Leitsch, 2019, PMID: 30617461). These radicals cause catastrophic damage to the pathogen's DNA and proteins, which is the basis of the drug's antimicrobial activity (Samuelson, 1999, PMID: 10430924). Because the expression of these proteins is regulated by environmental iron levels, iron deficiency can lead to the down-regulation of the system, resulting in reduced drug activation and clinical resistance (Upcroft & Upcroft, 2001, PMID: 11226607). This system is therefore a critical therapeutic target and a major factor in the efficacy of treatments for infections like trichomoniasis, giardiasis, and amoebiasis.

Other names

Hydrogenosomal redox chainNitroimidazole activation pathwayPFOR-ferredoxin pathwayIron-regulated nitroreductase system

Reductive activation of nitroimidazole prodrugs into reactive radical species