Alterations in chromosomal genes , , and are associated with nitrofurantoin resistance in from the United Kingdom.

Antimicrobial resistance in enteric or urinary is a risk factor for invasive infections. Due to widespread trimethoprim resistance amongst urinary and increased bacteraemia incidence, a national recommendation to prescribe nitrofurantoin for uncomplicated urinary tract infection was made in 2014. Nitrofurantoin resistance is reported in <6% urinary isolates in the UK, however, mechanisms underpinning nitrofurantoin resistance in these isolates remain unknown. This study aimed to identify the genetic basis of nitrofurantoin resistance in urinary isolates collected from north west London and then elucidate resistance-associated genetic alterations in available UK genomes. As a result, an algorithm was developed to predict nitrofurantoin susceptibility. Deleterious mutations and gene-inactivating insertion sequences in chromosomal nitroreductase genes and/or were identified in genomes of nine confirmed nitrofurantoin-resistant urinary isolates and additional 11 isolates that were highlighted by the prediction algorithm and subsequently validated to be nitrofurantoin-resistant. Eight categories of allelic changes in , , and the associated gene were detected in 12412 genomes from the UK. Evolutionary analysis of these three genes revealed homoplasic mutations and explained the previously reported order of stepwise mutations. The mobile gene complex , which is associated with reduced nitrofurantoin susceptibility, was identified in only one of the 12412 genomes. In conclusion, mutations and insertion sequences in and were leading causes of nitrofurantoin resistance in UK . As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage isolates and those from urinary and bloodstream infections should be monitored.