Bacterial nitroreductase (NTR) (NTR)

Bacterial nitroreductases (NTRs) are a diverse family of flavin-dependent enzymes that catalyze the reduction of nitroaromatic and nitroheterocyclic compounds using NAD(P)H as an electron donor [PubMed, 2021]. These enzymes are broadly classified into Type I (oxygen-insensitive) and Type II (oxygen-sensitive) categories, with Type I enzymes being particularly significant for their role in prodrug activation [NIH, 2008]. In clinical practice, NTRs are the primary targets for the bioactivation of several antimicrobial agents, including metronidazole, nitrofurantoin, and the anti-tuberculosis drugs pretomanid and delamanid [NIH, 2021]. Upon reduction by the enzyme, these prodrugs are converted into highly reactive intermediates, such as hydroxylamines or radicals, which cause lethal damage to bacterial DNA and proteins [EBI, 2021]. In addition to their role in treating infections, bacterial nitroreductases are a cornerstone of Gene-Directed Enzyme Prodrug Therapy (GDEPT) for cancer [PubMed, 2013]. In this strategy, bacterial NTR genes are delivered to tumor cells to facilitate the localized activation of non-toxic prodrugs like CB1954, thereby minimizing systemic toxicity [ResearchGate, 2016]. NTRs also serve as important biomarkers for tumor hypoxia and are utilized in environmental bioremediation to degrade nitro-substituted pollutants [Wikipedia, 2024]. However, the therapeutic utility of these enzymes is often challenged by the development of resistance through gene mutations and the potential for off-target effects caused by the diffusion of toxic metabolites [NIH, 2021].

Other names

Oxygen-insensitive NAD(P)H nitroreductaseType I nitroreductaseType II nitroreductaseNfsANfsBDdn (Deazaflavin-dependent nitroreductase)RdxAFrxAFlavin-dependent nitroreductaseAzoreductase (AzoR)N-ethylmaleimide reductase (NemA)Modulator of drug activity B (MdaB)

Bacterial nitroreductases catalyze the reductive bioactivation of nitro-containing prodrugs by transferring electrons from NAD(P)H to the nitro group of the substrate. This process generates reactive intermediates, such as nitroso and hydroxylamine derivatives, which are highly cytotoxic. These reactive species interact with cellular macromolecules, leading to DNA adduct formation, strand breaks, and protein damage, which ultimately results in the death of the target organism or cell [EBI, 2021; NIH, 2021].