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首页> 外文期刊>EBioMedicine >Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine
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Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine

机译：尿液生长过程中高水平美西林对大肠杆菌易感性的逆转

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Mecillinam (amdinocillin) is a @b-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (Mec^R) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were Mec^R due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, Mec^RE. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the Mec^R mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as Mec^R in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting Mec^RE. coli strain and thereby increase treatment efficiency.
机译：Mecillinam（amdinocillin）是@ b-内酰胺类抗生素，用于治疗单纯性尿路感染（UTI）。先前我们已经表明，大肠杆菌cysB基因的失活是临床分离株中美西林抗性（Mec ^ R）的主要原因。在这项研究中，我们使用了由于cysB突变而成为Mec ^ R的不同大肠杆菌菌株（实验室和临床分离株）来确定尿液中美西林的易感性与常用生长培养基Mueller Hinton（MHB）的生长相比如何受到影响。 ）。我们还检查了从48位不同健康志愿者获得的尿液中细菌生长时的美西林敏感性。对尿液样本进行了代谢组分析，并研究了细菌的美西林敏感性模式与尿液代谢产物水平之间的关联。报告了两个具有临床意义的主要发现。首先，Mec ^ RE。与实验室培养基相比，当在尿中生长时，大肠杆菌cysB突变株（实验室和临床分离株）总是对美西林敏感，许多菌株在尿液中表现出完全的表型敏感性。其次，在从不同个体获得的尿液样本之间，药敏性的恢复程度也有所不同。这种差异与重量克分子渗透压浓度相关，因此，在克分子渗透压浓度低的尿液中，与高克分子渗透压浓度的尿液相比，Mec ^ R突变体更容易接受美西林。这是描述条件抗性的第一个例子，其中遗传稳定的抗生素抗性可以通过尿液中存在的代谢物在表型上转化为易感性。这些发现对使用美西林治疗UTI有重要的临床意义。首先，他们建议美西林可以用于治疗那些在标准实验室测试中被鉴定为Mec ^ R的临床菌株。其次，结果表明，应该在模拟尿液的培养基中进行实验室对美西林的药敏试验，以获得与临床相关的药敏试验结果。第三，这些发现暗示患者行为的改变，例如增加饮水量或使用利尿剂以减少尿渗透压和增加半胱氨酸的摄入量，可能会在感染的MecRE中引起抗生素敏感性。大肠杆菌菌株，从而提高治疗效率。

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