Biosynthesis of Aurodox, a Type III Secretion System Inhibitor from Streptomyces goldiniensis.
Biosynthesis of Aurodox, a Type III Secretion System Inhibitor from Streptomyces goldiniensis.
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DOI：
10.1128/aem.00692-22
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发表时间：
2022-08-09
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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全球耐药性感染的增加意味着需要开发新的抗菌分子和策略来解决这个问题。Aurodox是由Streptomyces goldiniensis产生的线性聚酮化合物天然产物，但对Aurodox的生物合成或编码其产生的生物合成基因簇（BGC）的性质知之甚少。为了更深入地了解S. goldiniensis的全基因组测序结果表明，存在一个87 kb的杂合聚酮合酶/非核糖体肽合成酶（PKS/NRPS）BGC。aurodox BGC与S.第365章.然而，BGC的遗传结构显著不同。候选的aurodox基因簇被克隆并在异源宿主中表达，以证明它负责aurodox的生物合成，并且破坏初级PKS基因（aurAI）废除了aurodox的生产。这些数据支持了一个模型，即参与aurodox生物合成的初始核心生物合成反应遵循kirromycin的反应。从S. goldiniensis中表达，并在kirromycin生产菌S. collinus T β 365使吡啶酮基团甲基化，表明这是生物合成的最后一步。该甲基化步骤也足以赋予aurodox独特的III型分泌系统抑制特性。肠出血性大肠杆菌（EHEC）是一种重要的全球性病原体，不建议使用传统的抗生素治疗。Aurodox通过特异性靶向III型分泌系统抑制EHEC在宿主肠道中建立感染的能力，同时避免与传统抗生素相关的毒素产生的诱导。这些性质表明，金诺霉素可能是一种很有前途的抗肠出血性大肠杆菌毒力化合物，值得进一步研究。在这里，我们的特征在于aurodox生物合成基因簇从链霉菌goldiniensis和建立的关键酶促步骤aurodox生物合成，产生独特的抗毒力活性。这些数据为未来的化学和遗传方法提供了基础，以生产具有更高功效和工程化新型艾法霉素潜力的aurodox衍生物。
The global increase in antimicrobial-resistant infections means that there is a need to develop new antimicrobial molecules and strategies to combat the issue. Aurodox is a linear polyketide natural product that is produced by Streptomyces goldiniensis, yet little is known about aurodox biosynthesis or the nature of the biosynthetic gene cluster (BGC) that encodes its production. To gain a deeper understanding of aurodox biosynthesis by S. goldiniensis, the whole genome of the organism was sequenced, revealing the presence of an 87 kb hybrid polyketide synthase/non-ribosomal peptide synthetase (PKS/NRPS) BGC. The aurodox BGC shares significant homology with the kirromycin BGC from S. collinus Tϋ 365. However, the genetic organization of the BGC differs significantly. The candidate aurodox gene cluster was cloned and expressed in a heterologous host to demonstrate that it was responsible for aurodox biosynthesis and disruption of the primary PKS gene (aurAI) abolished aurodox production. These data supported a model whereby the initial core biosynthetic reactions involved in aurodox biosynthesis followed that of kirromycin. Cloning aurM* from S. goldiniensis and expressing this in the kirromycin producer S. collinus Tϋ 365 enabled methylation of the pyridone group, suggesting this is the last step in biosynthesis. This methylation step is also sufficient to confer the unique type III secretion system inhibitory properties to aurodox. IMPORTANCE Enterohemorrhagic Escherichia coli (EHEC) is a significant global pathogen for which traditional antibiotic treatment is not recommended. Aurodox inhibits the ability of EHEC to establish infection in the host gut through the specific targeting of the type III secretion system while circumventing the induction of toxin production associated with traditional antibiotics. These properties suggest aurodox could be a promising anti-virulence compound for EHEC, which merits further investigation. Here, we characterized the aurodox biosynthetic gene cluster from Streptomyces goldiniensis and established the key enzymatic steps of aurodox biosynthesis that give rise to the unique anti-virulence activity. These data provide the basis for future chemical and genetic approaches to produce aurodox derivatives with increased efficacy and the potential to engineer novel elfamycins.
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