Microbial nitroreductase and low-redox-potential ferredoxin-like electron transfer protein (NTR/Fd)

Microbial nitroreductases (NTRs) and low-redox-potential ferredoxin-like electron transfer proteins constitute a critical metabolic pathway in anaerobic and microaerophilic microorganisms (Müller, 1988). These enzymes are responsible for the reduction of nitrogen-containing compounds, playing a vital role in cellular redox homeostasis and anaerobic energy metabolism (Leitsch, 2017). In a clinical context, this system is the primary target for 5-nitroimidazole antibiotics, such as metronidazole, which act as prodrugs. The low-redox-potential environment provided by ferredoxins allows for the specific reduction of the nitro group on these drugs, generating highly reactive radical intermediates that induce DNA strand breaks and cell death (Goodwin et al., 1998). Beyond infectious diseases, this system is being explored in Gene-Directed Enzyme Prodrug Therapy (GDEPT) for cancer, where microbial NTR genes are delivered to tumor cells to locally activate chemotherapeutic agents like CB1954 (Williams et al., 2015). Resistance to these drugs often arises through mutations in the genes encoding these nitroreductases or their associated electron donors.

Other names

NitroreductaseFerredoxinType I nitroreductaseType II nitroreductaseRdxAFrxAOxygen-insensitive nitroreductaseOxygen-sensitive nitroreductase

The system catalyzes the multi-step reduction of the nitro group of prodrugs (e.g., 5-nitroimidazoles) to reactive nitroso and hydroxylamine intermediates, which subsequently form covalent adducts with DNA or cause strand breakage (Müller, 1988; Leitsch, 2017).