Nitrofurantoin: mechanism of action and implications for resistance development in common uropathogens

Nitrofurantoin is an effective urinary tract antibacterial to which no clinically significant resistance development has occurred. We have previously shown that nitrofurantoin susceptibility in bacteria correlates with the presence of bacterial nitroreductases which convert nitrofurantoin to highly reactive electrophilic intermediates. These intermediates were shown to attack bacterial ribosomal proteins non-specifically, causing complete inhibition of protein synthesis. In the present study, we confirm previous reports that low concentrations of nitrofurantoin specifically inhibit inducible enzyme synthesis in bacteria, and show that this inhibition occurs at levels equivalent to the MICs of nitrofurantoin for several bacterial species. Our previous studies had shown that nitrofurantoin at different concentrations interacts with bacterial ribosomal proteins in qualitatively the same fashion; we now report that quantitative differences are seen in the labelling observed at different nitrofurantoin concentrations and discuss these differences as they may relate to the inhibition of inducible enzyme synthesis. In addition, we have now demonstrated the existence of a novel mechanism of action for nitrofurantoin which does not require the production of reactive nitrofurantoin metabolites by bacterial reductases. The lack of clinically significant bacterial resistance development to nitrofurantoin is likely due to the combination of nitrofurantoin's multiple sites of attack and multiple mechanisms of action.