Kanglemycin A Can Overcome Rifamycin Resistance Caused by ADP-Ribosylation by Arr Protein.
Kanglemycin A Can Overcome Rifamycin Resistance Caused by ADP-Ribosylation by Arr Protein.
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DOI：
10.1128/aac.00864-21
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发表时间：
2021-11-17
影响因子：
4.9
通讯作者：
Zenkin N
中科院分区：
文献类型：
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作者：
Harbottle J;Mosaei H;Allenby N;Zenkin N
利福霉素，如利福平（Rif），是细菌RNA聚合酶（RNAP）的有效抑制剂，是广泛使用的抗生素。利福霉素耐药性通常与RNAP突变相关，该突变阻止了利福霉素结合。然而，一些细菌具有一种ADP-核糖基转移酶Arr，其ADP-核糖基化利福霉素分子，从而使其抗微生物活性失活。在这里，我们直接表明，ADP-核糖基化废除利福平，最广泛使用的利福霉素抗生素的转录抑制。我们还表明，天然的利福霉素，康乐霉素A（KglA），它有一个独特的糖部分在柄链接近的Arr修饰位点，不结合到Arr从耻垢分枝杆菌，因此不容易失活。然而，我们发现，康乐霉素A仍然可以被一种新出现的病原体，分枝杆菌的Arr腺苷二磷酸核糖基化。有趣的是，Arr中唯一在物种间没有同源性的部分是与M中康乐霉素A的糖部分空间冲突的部分。斯迈吉这表明M。在进化过程中，KglA或利福霉素也遇到过类似的糖修饰。结果表明，KglA可能是一种有效的抗微生物剂对一些Arr编码细菌。
Rifamycins, such as rifampicin (Rif), are potent inhibitors of bacterial RNA polymerase (RNAP) and are widely used antibiotics. Rifamycin resistance is usually associated with mutations in RNAP that preclude rifamycin binding. However, some bacteria have a type of ADP-ribosyl transferases, Arr, which ADP-ribosylate rifamycin molecules, thus inactivating their antimicrobial activity. Here, we directly show that ADP-ribosylation abolishes inhibition of transcription by rifampicin, the most widely used rifamycin antibiotic. We also show that a natural rifamycin, kanglemycin A (KglA), which has a unique sugar moiety at the ansa chain close to the Arr modification site, does not bind to Arr from Mycobacterium smegmatis and thus is not susceptible to inactivation. We, found, however, that kanglemycin A can still be ADP-ribosylated by the Arr of an emerging pathogen, Mycobacterium abscessus. Interestingly, the only part of Arr that exhibits no homology between the species is the part that sterically clashes with the sugar moiety of kanglemycin A in M. smegmatis Arr. This suggests that M. abscessus has encountered KglA or rifamycin with a similar sugar modification in the course of evolution. The results show that KglA could be an effective antimicrobial against some of the Arr-encoding bacteria.