Inactivation mechanisms of antibiotic by pathogenic Nocardia and related taxa

我们曾报道致病性诺卡菌对大环内酯类抗生素和利福平表现出物种特异性耐药模式。对5种诺卡菌对3种大环内酯类药物（红霉素、罗基他霉素和midecycin）的敏感性进行了调查，结果表明诺卡菌对3种大环内酯类药物具有不同的敏感性。大部分抗性是由于大环内酯类化合物通过磷酸化、糖基化、还原和去酰化或两者的结合而失活。对利福平失活的研究表明，利福平是通过磷酸化和糖基化失活的。此外，我们还在其他抗酸细菌如分枝杆菌中发现了一种新的失活机制。几种快速生长的分枝杆菌菌株被发现能灭活利福平。这些生物产生的两种灭活化合物不同于先前报道的衍生物，即抗生素的磷酸化或糖基化衍生物。两种化合物的结构分别为3-甲酰基-23-[O- d -核糖呋喃基]利福霉素SV和23-[O-（α - d -核糖呋喃基）]利福平。据我们所知，这是核糖基化作为抗生素失活机制的第一个已知例子。我们最近的研究表明，NADH作为底物在核糖基化过程中是必不可少的。我们还得到了两个可能导致核糖基化的中间化合物，它们的分子量分别为1034和1363。目前，对与核糖化活性相关的基因和中间体结构测定的详细研究正在进行中。

We had reported that pathogenic Nocardia showed species-specific resistant patterns against macrolide antibiotics and rifampicin. A survey of five Nocardia spp. with respect to susceptibility towards three macrolides (erythromycin, rokitamycin and midecemycin) showed that the Nocardia spp. have different susceptibility profiles. Most of the resistance was due to the inactivation of the macrolides by phosphorylation, glucosylation, reduction and deacylation, or combination of there of. The studies on the rifampicin inactivation showed that rifampicin was inactivated by phosphorylation and glucosylation. In addition, we also find a new inactivation mechanism in other acid-fast bacterium such as Mycobacterium. Severalfast-growing Mycobacterium strains were found to inactivate rifampicin. Two inactivated compounds produced by these organisms were different from previously reported derivatives, i. e., phosphorylated or glucosylated derivatives of the antibiotic. The structures of two compounds were determined to be those of 3-formyl-23-[O-alpha-D-ribafuranosyl]rifamycin SV and 23-[O-(alpha-D-ribofuranosyl)]rifampicin, respectively. To our knowledge, this is the first known examples of ribosylation as a mechanism of antibiotic inactivation. Our recent studies indicated that NADH is a essential for the ribosylation as a substrate. We also obtained two possible intermediate compounds which lead to ribosylation and their molecular weights were found to be 1034 and 1363, respectively. Now detail studies on the gene (s) associated with ribosylation activity and structural determination of the intermediates are progress.