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首页> 外文期刊>Applied Microbiology >The ADEP Biosynthetic Gene Cluster in Streptomyces hawaiiensis NRRL 15010 Reveals an Accessory clpP Gene as a Novel Antibiotic Resistance Factor
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The ADEP Biosynthetic Gene Cluster in Streptomyces hawaiiensis NRRL 15010 Reveals an Accessory clpP Gene as a Novel Antibiotic Resistance Factor

机译：夏威夷链霉菌NRRL 15010中的ADEP生物合成基因簇揭示了附加的clpP基因作为新型抗生素抗性因子

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The increasing threat posed by multiresistant bacterial pathogens necessitates the discovery of novel antibacterials with unprecedented modes of action. ADEP1, a natural compound produced by Streptomyces hawaiiensis NRRL 15010, is the prototype for a new class of acyldepsipeptide (ADEP) antibiotics. ADEP antibiotics deregulate the proteolytic core ClpP of the bacterial caseinolytic protease, thereby exhibiting potent antibacterial activity against Gram-positive bacteria, including multiresistant pathogens. ADEP1 and derivatives, here collectively called ADEP, have been previously investigated for their antibiotic potency against different species, structure-activity relationship, and mechanism of action; however, knowledge on the biosynthesis of the natural compound and producer self-resistance have remained elusive. In this study, we identified and analyzed the ADEP biosynthetic gene cluster in S. hawaiiensis NRRL 15010, which comprises two NRPSs, genes necessary for the biosynthesis of (4S,2R)-4-methylproline, and a type II polyketide synthase (PKS) for the assembly of highly reduced polyenes. While no resistance factor could be identified within the gene cluster itself, we discovered an additional clpP homologous gene (named clpPADEP) located further downstream of the biosynthetic genes, separated from the biosynthetic gene cluster by several transposable elements. Heterologous expression of ClpPADEP in three ADEP-sensitive Streptomyces species proved its role in conferring ADEP resistance, thereby revealing a novel type of antibiotic resistance determinant.IMPORTANCE Antibiotic acyldepsipeptides (ADEPs) represent a promising new class of potent antibiotics and, at the same time, are valuable tools to study the molecular functioning of their target, ClpP, the proteolytic core of the bacterial caseinolytic protease. Here, we present a straightforward purification procedure for ADEP1 that yields substantial amounts of the pure compound in a time- and cost-efficient manner, which is a prerequisite to conveniently study the antimicrobial effects of ADEP and the operating mode of bacterial ClpP machineries in diverse bacteria. Identification and characterization of the ADEP biosynthetic gene cluster in Streptomyces hawaiiensis NRRL 15010 enables future bioinformatics screenings for similar gene clusters and/or subclusters to find novel natural compounds with specific substructures. Most strikingly, we identified a cluster-associated clpP homolog (named clpPADEP) as an ADEP resistance gene. ClpPADEP constitutes a novel bacterial resistance factor that alone is necessary and sufficient to confer high-level ADEP resistance to Streptomyces across species.
机译：由多重抗药性细菌病原体构成的威胁日益增加，因此有必要发现具有前所未有作用方式的新型抗菌剂。 ADEP1是夏威夷链霉菌NRRL 15010产生的天然化合物，是一类新型脂肽肽（ADEP）抗生素的原型。 ADEP抗生素可解除细菌酪蛋白水解蛋白酶的蛋白水解核心ClpP的调控，从而对革兰氏阳性细菌（包括多重耐药病原体）表现出强大的抗菌活性。以前已经对ADEP1及其衍生物（以下统称为ADEP）进行了研究，以了解它们对不同物种，结构与活性的关系以及作用机理的抗药性。然而，关于天然化合物的生物合成和生产者自身抗性的知识仍然难以捉摸。在这项研究中，我们鉴定和分析了夏威夷葡萄球菌NRRL 15010中的ADEP生物合成基因簇，该簇包含两个NRPS，（4S，2R）-4-甲基脯氨酸生物合成所必需的基因和II型聚酮化合物合酶（PKS）用于组装高度还原的多烯。虽然无法在基因簇本身中鉴定出抗性因子，但我们发现了一个位于生物合成基因下游的额外clpP同源基因（名为clpPADEP），通过几个可转座元件与生物合成基因簇隔开。 ClpPADEP在三种对ADEP敏感的链霉菌种中的异源表达证明了其在赋予ADEP耐药性中的作用，从而揭示了一种新型的抗生素耐药性决定子。是研究靶标ClpP分子功能的重要工具，ClpP是细菌酪蛋白水解蛋白酶的蛋白水解核心。在这里，我们介绍了一种简单的ADEP1纯化程序，该程序可以以省时省钱的方式生产大量纯净的化合物，这是方便地研究ADEP的抗菌作用和各种细菌ClpP机械操作模式的前提菌。夏威夷链霉菌NRRL 15010中ADEP生物合成基因簇的鉴定和表征，使得将来对相似基因簇和/或亚簇的生物信息学筛选能够发现具有特定亚结构的新型天然化合物。最引人注目的是，我们确定了与簇相关的clpP同源物（称为clpPADEP）作为ADEP抗性基因。 ClpPADEP构成了一种新颖的细菌抗性因子，仅此一个因子就足以使整个物种对链霉菌具有高水平的ADEP抗性。

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