Centre for Bacterial Cell Biology, Biosciences Institute, Faculty of Medical Sciences, Newcastle Universitygrid.1006.7, Newcastle upon Tyne, United Kingdom.
Odyssey Newcastle, The Biosphere, Draymans Way, Newcastle upon Tyne, United Kingdom.
Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0086421. doi: 10.1128/AAC.00864-21. Epub 2021 Oct 4.
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 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.
利福霉素类药物，如利福平（Rif），是强效的细菌 RNA 聚合酶（RNAP）抑制剂，被广泛用作抗生素。利福霉素耐药性通常与 RNAP 突变相关，这些突变阻止了利福霉素的结合。然而，一些细菌具有一种 ADP-核糖基转移酶 Arr，它将 ADP-核糖基化利福霉素分子，从而使其丧失抗菌活性。在这里，我们直接表明 ADP-核糖基化会使 rifampicin（最广泛使用的利福霉素抗生素）对转录的抑制作用丧失。我们还表明，一种天然的利福霉素，即康莱霉素 A（KglA），在靠近 Arr 修饰位点的链上具有独特的糖部分，不会与分枝杆菌中的 Arr 结合，因此不易失活。然而，我们发现康莱霉素 A 仍然可以被新兴病原体脓肿分枝杆菌的 Arr 进行 ADP-核糖基化。有趣的是，Arr 中唯一在物种之间没有同源性的部分是与分枝杆菌 Arr 中康莱霉素 A 的糖部分在空间上发生冲突的部分。这表明脓肿分枝杆菌在进化过程中已经遇到了具有类似糖修饰的 KglA 或利福霉素。结果表明，KglA 可能是针对某些编码 Arr 的细菌的有效抗菌药物。
