Table_8_Antibiotic Production and Antibiotic Resistance: The Two Sides of AbrB1/B2, a Two-Component System of Streptomyces coelicolor.pdf

Antibiotic resistance currently presents one of the biggest threats to humans. The development and implementation of strategies against the spread of superbugs is a priority for public health. In addition to raising social awareness, approaches such as the discovery of new antibiotic molecules and the elucidation of resistance mechanisms are common measures. Accordingly, the two-component system (TCS) of Streptomyces coelicolor AbrB1/B2, offer amenable ways to study both antibiotic production and resistance. Global transcriptomic comparisons between the wild-type strain S. coelicolor M145 and the mutant ΔabrB, using RNA-Seq, showed that the AbrB1/B2 TCS is implicated in the regulation of different biological processes associated with stress responses, primary and secondary metabolism, and development and differentiation. The ΔabrB mutant showed the up-regulation of antibiotic biosynthetic gene clusters and the down-regulation of the vancomycin resistance gene cluster, according to the phenotypic observations of increased antibiotic production of actinorhodin and undecylprodigiosin, and greater susceptibility to vancomycin. The role of AbrB1/B2 in vancomycin resistance has also been shown by an in silico analysis, which strongly indicates that AbrB1/B2 is a homolog of VraR/S from Staphylococcus aureus and LiaR/S from Enterococcus faecium/Enterococcus faecalis, both of which are implied in vancomycin resistance in these pathogenic organisms that present a serious threat to public health. The results obtained are interesting from a biotechnological perspective since, on one hand, this TCS is a negative regulator of antibiotic production and its high degree of conservation throughout Streptomyces spp. makes it a valuable tool for improving antibiotic production and the discovery of cryptic metabolites with antibiotic action. On the other hand, AbrB1/B2 contributes to vancomycin resistance and is a homolog of VraR/S and LiaR/S, important regulators in clinically relevant antibiotic-resistant bacteria. Therefore, the study of AbrB1/B2 could provide new insight into the mechanism of this type of resistance.

抗生素耐药性目前对人类构成了最大的威胁之一。针对超级细菌传播的策略研发与实施是公共卫生领域的当务之急。除了提升社会公众意识之外，发现新型抗生素分子以及阐明耐药机制也是常见的应对措施。据此，由放线菌属 Streptomyces coelicolor 的 AbrB1/B2 双组分系统（TCS）提供的途径，为研究抗生素产生与耐药性提供了便利。通过 RNA-Seq 技术对野生型菌株 S. coelicolor M145 与突变型 ΔabrB 进行全局转录组比较，揭示了 AbrB1/B2 TCS 在调节与压力反应、初级与次级代谢、以及发育与分化相关的多种生物过程中的作用。根据对突变型 ΔabrB 的表型观察，包括抗生素生产增加的放线菌红素和十一烷基prodigiosin，以及对万古霉素的更高敏感性，发现其抗生素生物合成基因簇上调，而万古霉素耐药基因簇下调。通过计算机模拟分析，还表明 AbrB1/B2 在万古霉素耐药性中扮演着重要角色，该分析强烈暗示 AbrB1/B2 是金黄色葡萄球菌中的 VraR/S 和粪肠球菌/粪链球菌中的 LiaR/S 的同源物，这两种同源物均与这些对公共卫生构成严重威胁的致病菌中的万古霉素耐药性有关。从生物技术角度来看，这些结果引人注目，一方面，该 TCS 作为抗生素生产的负调节因子，其在放线菌属中高度保守的特性使其成为提高抗生素生产力和发现具有抗生素活性的隐秘代谢物的宝贵工具；另一方面，AbrB1/B2 对万古霉素耐药性有所贡献，并且是 VraR/S 和 LiaR/S 的同源物，这两者在临床上相关的耐药细菌中是重要的调节因子。因此，对 AbrB1/B2 的研究可能为揭示此类耐药性机制提供新的见解。