Pharmaceutical Institute, Department of Pharmaceutical Biology, University of Tübingengrid.10392.39, Tübingen, Germany.
Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Microbiol Spectr. 2022 Jun 29;10(3):e0049322. doi: 10.1128/spectrum.00493-22. Epub 2022 May 5.
Antibiotic-producing microorganisms usually require one or more self-resistance determinants to survive antibiotic production. The effectors of these mechanisms are proteins that inactivate the antibiotic, facilitate its transport, or modify the target to render it insensitive to the molecule. Streptomyces bacteria biosynthesize various bioactive natural products and possess resistance systems for most metabolites, which are coregulated with antibiotic biosynthesis genes. Streptomyces olindensis strain DAUFPE 5622 produces the antitumor antibiotic cosmomycin D (COSD), a member of the anthracycline family. In this study, we propose three self-resistance mechanisms, anchored or based in the COSD biosynthetic gene cluster. These include (an ABC transporter), (a UvrA class IIa protein), and a new self-resistance mechanism encoded by , which shows response against peroxides by the enzyme mycothiol peroxidase (MPx). Activity-based investigations of MPx and its mutant enzyme confirmed peroxidation during the production of COSD. Overexpression of the ABC transporter, the UvrA class IIa protein, and the MPx led to an effective response against toxic anthracyclines, such as cosmomycins. Our findings help to understand how thiol peroxidases play an antioxidant role in the anthracycline producer S. olindensis DAUFPE 5622, a mechanism which has been reported for neoplastic cells that are resistant to doxorubicin (DOX). Anthracycline compounds are DNA intercalating agents widely used in cancer chemotherapeutic protocols. This work focused on the self-resistance mechanisms developed by the cosmomycin-producing bacterium Streptomyces olindensis. Our findings showed that cysteine peroxidases, such as mycothiol peroxidase, encoded by the gene , protected S. olindensis against peroxidation during cosmomycin production. This observation can contribute to much better understanding of resistance both in the producers, eventually enhancing production, and in some tumoral cell lines.
产生抗生素的微生物通常需要一个或多个自我抗性决定因素才能在抗生素产生过程中存活下来。这些机制的效应物是使抗生素失活、促进其运输或修饰靶标以使靶标对分子不敏感的蛋白质。链霉菌细菌生物合成各种生物活性天然产物，并拥有大多数代谢物的抗性系统，这些系统与抗生素生物合成基因共同调控。链霉菌 olindensis 菌株 DAUFPE 5622 产生抗肿瘤抗生素 cosmomycin D (COSD)，属于蒽环类抗生素家族。在这项研究中，我们提出了三种自我抗性机制，锚定或基于 COSD 生物合成基因簇。这些机制包括 (ABC 转运蛋白)、 (UvrA 类 IIa 蛋白) 和由 编码的新的自我抗性机制，该机制通过酶 mycothiol peroxidase (MPx) 对过氧化物表现出反应。MPx 及其突变酶的基于活性的研究证实了 COSD 产生过程中的过氧化物形成。ABC 转运蛋白、UvrA 类 IIa 蛋白和 MPx 的过表达导致对毒性蒽环类抗生素（如 cosmomycins）的有效反应。我们的发现有助于理解硫醇过氧化物酶如何在对阿霉素（DOX）有抗性的肿瘤细胞中发挥抗氧化作用，这一机制已在蒽环类抗生素产生菌 S. olindensis DAUFPE 5622 中报道。蒽环类化合物是广泛用于癌症化疗方案的 DNA 插入剂。这项工作侧重于产生 cosmomycin 的细菌 Streptomyces olindensis 开发的自我抗性机制。我们的发现表明，由基因 编码的半胱氨酸过氧化物酶，如 mycothiol peroxidase，在 cosmomycin 产生过程中保护 S. olindensis 免受过氧化物的侵害。这一观察结果可以为在生产者中、最终提高生产效率以及在某些肿瘤细胞系中对抗性有更深入的了解做出贡献。
