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首页> 外文期刊>Antimicrobial agents and chemotherapy. >An in Vitro deletion in ribE encoding lumazine synthase contributes to nitrofurantoin resistance in Escherichia coli
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An in Vitro deletion in ribE encoding lumazine synthase contributes to nitrofurantoin resistance in Escherichia coli

机译：编码lumazine合酶的ribE的体外缺失有助于大肠杆菌中的呋喃妥因抗性

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Nitrofurantoin has been used for decades for the treatment of urinary tract infections (UTIs), but clinically significant resistance in Escherichia coli is uncommon. Nitrofurantoin concentrations in the gastrointestinal tract tend to be low, which might facilitate selection of nitrofurantoin-resistant (NIT-R) strains in the gut flora. We subjected two nitrofurantoin-susceptible intestinal E. coli strains (ST540-p and ST2747-p) to increasing nitrofurantoin concentrations under aerobic and anaerobic conditions. Whole-genome sequencing was performed for both susceptible isolates and selected mutants that exhibited the highest nitrofurantoin resistance levels aerobically (ST540-a and ST2747-a) and anaerobically (ST540-an and ST2747-an). ST540-a/ST540-an and ST2747-a (aerobic MICs of >64 μg/ml) harbored mutations in the known nitrofurantoin resistance determinants nfsA and/or nfsB, which encode oxygen-insensitive nitroreductases. ST2747-an showed reduced nitrofurantoin susceptibility (aerobic MIC of 32 μg/ml) and exhibited remarkable growth deficits but did not harbor nfsAfsB mutations. We identified a 12-nucleotide deletion in ribE, encoding lumazine synthase, an essential enzyme involved in the biosynthesis of flavin mononucleotide (FMN), which is an important cofactor for NfsA and NfsB. Complementing ST2747-an with a functional wild-type lumazine synthase restored nitrofurantoin susceptibility. Six NIT-R E. coli isolates (NRCI-1 to NRCI-6) from stools of UTI patients treated with nitrofurantoin, cefuroxime, or a fluoroquinolone harbored mutations in nfsA and/or nfsB but not ribE. Sequencing of the ribE gene in six intestinal and three urinary E. coli strains showing reduced nitrofurantoin susceptibility (MICs of 16 to 48 μg/ml) also did not identify any relevant mutations. NRCI-1, NRCI-2, and NRCI-5 exhibited up to 4-fold higher anaerobic MICs, compared to the mutants generated in vitro, presumably because of additional mutations in oxygen-sensitive nitroreductases.
机译：呋喃妥因已被用于治疗尿路感染（UTI）数十年，但在大肠杆菌中临床上显着的耐药性并不常见。胃肠道中呋喃妥因的浓度往往较低，这可能有助于在肠道菌群中选择耐呋喃妥因（NIT-R）菌株。在有氧和无氧条件下，我们对两种对呋喃妥因敏感的肠道大肠杆菌菌株（ST540-p和ST2747-p）进行了增加的呋喃妥因浓度的调整。对有氧菌株（ST540-a和ST2747-a）和厌氧菌（ST540-an和ST2747-an）表现出最高的呋喃妥因抗性水平的易感菌株和选定突变体进行全基因组测序。 ST540-a / ST540-an和ST2747-a（需氧MIC> 64μg/ ml）在已知的呋喃妥因抗性决定簇nfsA和/或nfsB中包含突变，它们编码对氧不敏感的硝基还原酶。 ST2747-an表现出降低的呋喃妥因敏感性（好氧MIC为32μg/ ml），并显示出明显的生长缺陷，但未携带nfsA / nfsB突变。我们在ribE中鉴定了12个核苷酸的缺失，编码lumazine合酶，这是一种与黄素单核苷酸（FMN）的生物合成有关的必需酶，它是NfsA和NfsB的重要辅助因子。 ST2747-an与功能性野生型lumazine合酶的补充恢复了呋喃妥因的敏感性。从用呋喃妥因，头孢呋辛或氟喹诺酮治疗的尿路感染患者的粪便中检出的6种NIT-R大肠杆菌分离株（NRCI-1至NRCI-6）在nfsA和/或nfsB中具有突变，但在ribE中没有突变。在显示出降低的呋喃妥因敏感性（MIC为16至48μg/ ml）的6个肠道和3个尿液大肠杆菌菌株中，ribE基因的测序也未发现任何相关突变。与体外产生的突变体相比，NRCI-1，NRCI-2和NRCI-5的厌氧性MIC高4倍，这可能是由于氧敏感性硝基还原酶的其他突变所致。

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