Alterations in chromosomal genes nfsA, nfsB, and ribE are associated with nitrofurantoin resistance in Escherichia coli from the United Kingdom.

Antimicrobial resistance in enteric or urinary Escherichia coli is a risk factor for invasive E. coli infections. Due to widespread trimethoprim resistance amongst urinary E. coli 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 E. coli 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 E. coli isolates collected from north west London and then elucidate resistance-associated genetic alterations in available UK E. coli genomes. As a result, an algorithm was developed to predict nitrofurantoin susceptibility. Deleterious mutations and gene-inactivating insertion sequences in chromosomal nitroreductase genes nfsA and/or nfsB were identified in genomes of nine confirmed nitrofurantoin-resistant urinary E. coli isolates and additional 11 E. coli isolates that were highlighted by the prediction algorithm and subsequently validated to be nitrofurantoin-resistant. Eight categories of allelic changes in nfsA, nfsB, and the associated gene ribE were detected in 12412 E. coli 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 oqxAB, which is associated with reduced nitrofurantoin susceptibility, was identified in only one of the 12412 genomes. In conclusion, mutations and insertion sequences in nfsA and nfsB were leading causes of nitrofurantoin resistance in UK E. coli . As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage E. coli isolates and those from urinary and bloodstream infections should be monitored.

肠道或泌尿系统大肠杆菌的抗菌药物耐药性是侵袭性大肠杆菌感染的一个风险因素。由于泌尿系统大肠杆菌对甲氧苄啶的广泛耐药以及菌血症发病率的上升，2014年英国提出了针对单纯性尿路感染开具呋喃妥因的全国性建议。据报道，在英国，<6%的泌尿系统大肠杆菌分离株对呋喃妥因耐药，然而，这些分离株中呋喃妥因耐药的机制仍不清楚。本研究旨在确定从伦敦西北部收集的泌尿系统大肠杆菌分离株中呋喃妥因耐药的遗传基础，然后阐明英国现有大肠杆菌基因组中与耐药相关的遗传改变。结果，开发了一种算法来预测呋喃妥因敏感性。在9株经确认的呋喃妥因耐药泌尿系统大肠杆菌分离株以及另外11株被预测算法标记且随后经验证为呋喃妥因耐药的大肠杆菌分离株的基因组中，鉴定出染色体硝基还原酶基因nfsA和/或nfsB中的有害突变以及使基因失活的插入序列。在来自英国的12412个大肠杆菌基因组中检测到nfsA、nfsB以及相关基因ribE的8类等位基因变化。对这三个基因的进化分析揭示了同塑突变，并解释了先前报道的逐步突变顺序。与呋喃妥因敏感性降低相关的可移动基因复合体oqxAB仅在12412个基因组中的一个中被鉴定到。总之，nfsA和nfsB中的突变和插入序列是英国大肠杆菌中呋喃妥因耐药的主要原因。随着人群中呋喃妥因暴露的增加，应监测携带的大肠杆菌分离株以及来自泌尿系统和血流感染的大肠杆菌分离株中呋喃妥因耐药的流行情况。