Nitrofurans: Revival of an “old” drug class in the fight against antibiotic resistance

Identification of these nitrofuran-activating enzymes in E. coli and understanding their biology (physiological functions, regulation of protein expression/action, and enzyme–nitrofuran molecular interaction) would provide useful knowledge to facilitate development of new nitrofuran-based antibacterial therapies. [...]in the case of potential low expression of the activating enzyme, structure-based virtual screens with an ultra-large library [14] targeting the expression regulator of the candidate enzyme or targeting the enzyme allosteric site can be employed to seek the adjuvant molecules that up-regulate the enzyme expression or enhance the enzyme activity, respectively; these adjuvant molecules can be used with nitrofuran antibiotics for improved antibacterial potency. Alternatively, rational design of nitrofuran analogs such that they favorably bind to the redox active site of the activation enzyme through in silico enzyme–drug docking simulation, followed by experimental validation, may generate novel nitrofuran candidates that are different from clinically used nitrofuran drugs in the terms of prodrug activation and resistance mechanisms. Perhaps due to the reduced bacterial growth rate caused by the ribE mutation, mutations in this gene have not been reported in E. coli clinical isolates and are unlikely to pose a significant threat to the efficacy of nitrofuran treatment.