McOsker C C, Fitzpatrick P M
Anti-Infective Research Department, Procter & Gamble Pharmaceuticals, Norwich, NY 13815.
J Antimicrob Chemother. 1994 May;33 Suppl A:23-30. doi: 10.1093/jac/33.suppl_a.23.
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.
呋喃妥因是一种有效的泌尿道抗菌药物，尚未出现临床上显著的耐药性发展情况。我们之前已经表明，细菌对呋喃妥因的敏感性与细菌硝基还原酶的存在相关，这些酶将呋喃妥因转化为高反应性的亲电中间体。这些中间体被证明会非特异性地攻击细菌核糖体蛋白，导致蛋白质合成完全抑制。在本研究中，我们证实了之前的报道，即低浓度的呋喃妥因会特异性抑制细菌中诱导酶的合成，并表明这种抑制发生在与几种细菌物种的呋喃妥因最低抑菌浓度相当的水平。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性质上是相同的；我们现在报告，在不同呋喃妥因浓度下观察到的标记存在定量差异，并讨论这些差异与诱导酶合成抑制可能的关系。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，该机制不需要细菌还原酶产生反应性呋喃妥因代谢物。临床上呋喃妥因未出现显著的细菌耐药性发展可能是由于呋喃妥因的多个攻击位点和多种作用机制共同作用的结果。
