NITROFURANTOIN - MECHANISM OF ACTION AND IMPLICATIONS FOR RESISTANCE DEVELOPMENT IN COMMON UROPATHOGENS
NITROFURANTOIN - MECHANISM OF ACTION AND IMPLICATIONS FOR RESISTANCE DEVELOPMENT IN COMMON UROPATHOGENS
复制标题
DOI：
10.1093/jac/33.suppl_a.23
复制
发表时间：
1994-05-01
影响因子：
5.2
通讯作者：
FITZPATRICK, PM
中科院分区：
文献类型：
--
作者：
MCOSKER, CC;FITZPATRICK, PM
呋喃妥因是一种有效的尿路抗菌药物，未发生临床显著的耐药性发展。我们之前已经表明，细菌对呋喃妥英的敏感性与细菌硝基还原酶的存在有关，这种酶能将呋喃妥英转化为高活性的亲电中间体。这些中间产物被证明非特异性地攻击细菌核糖体蛋白，导致蛋白质合成的完全抑制。在本研究中，我们证实了先前的报道，即低浓度的呋喃妥因特异性地抑制细菌中诱导酶的合成，并表明这种抑制作用在几种细菌中发生的水平相当于呋喃妥因的mic。我们之前的研究表明，不同浓度的呋喃妥因与细菌核糖体蛋白的相互作用在质量上是相同的；我们现在报道，在不同呋喃妥因浓度下观察到的标记数量差异，并讨论这些差异，因为它们可能与诱导酶合成的抑制有关。此外，我们现在已经证明了呋喃妥因存在一种新的作用机制，它不需要细菌还原酶产生活性呋喃妥因代谢物。对呋喃妥英缺乏临床意义的细菌耐药性发展可能是由于呋喃妥英的多个攻击部位和多种作用机制的结合。
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.