Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes.
Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes.
复制标题
DOI：
10.1128/aem.02828-17
复制
发表时间：
2018-05-01
影响因子：
4.4
通讯作者：
Truman AW
中科院分区：
文献类型：
--
作者：
Vior NM;Lacret R;Chandra G;Dorai-Raj S;Trick M;Truman AW
双环霉素（Bicyclomycin，Bicyclomycin）是一种由肉桂链霉菌DSM 41675生物合成的具有临床应用前景的抗生素。BCM的结构特征是核心环（l-Ile-l-Leu）2，5-二酮哌嗪（DKP）被广泛氧化。在这里，我们确定的生物合成基因簇，这表明，核心的生物合成的环二肽合成酶，和氧化修饰引入5个2-酮戊二酸依赖性双加氧酶和细胞色素P450单加氧酶。该基因簇的发现使得能够鉴定由分布于全球的数百种铜绿假单胞菌分离株的基因组编码的β-内酰胺酶途径，并且来自铜绿假单胞菌SCV 20265的该途径的异源表达证明该产物在化学上与S.肉桂属。总的来说，已经在至少七个属中发现了推定的β-内酰胺酶基因簇，这些属跨越放线菌和变形菌（α-变形菌、β-变形菌和γ-变形菌）。这是一个罕见的例子，一个完整的生物合成基因簇的水平基因转移在这样的远亲细菌，我们表明，这些基因簇几乎总是与移动的遗传因素。重要信息双环霉素是唯一选择性抑制转录终止因子Rho的天然产物抗生素。这种作用机制，结合其已证实的生物安全性及其对临床相关革兰氏阴性细菌病原体的活性，使其成为非常有前途的抗生素候选物。在这里，我们报告的双环霉素生物合成基因簇的识别在已知的双环霉素生产生物体肉桂链霉菌，这将使新的双环霉素衍生物的工程生产。该基因簇的鉴定还导致发现了数百种在高度多样化的细菌中编码的双环霉素途径，包括在机会致病菌铜绿假单胞菌中。这种复杂的生物合成途径的广泛分布是非常不寻常的，并提供了一个深入了解抗生素的途径如何可以在不同的细菌之间转移。
Bicyclomycin (BCM) is a clinically promising antibiotic that is biosynthesized by Streptomyces cinnamoneus DSM 41675. BCM is structurally characterized by a core cyclo(l-Ile-l-Leu) 2,5-diketopiperazine (DKP) that is extensively oxidized. Here, we identify the BCM biosynthetic gene cluster, which shows that the core of BCM is biosynthesized by a cyclodipeptide synthase, and the oxidative modifications are introduced by five 2-oxoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase. The discovery of the gene cluster enabled the identification of BCM pathways encoded by the genomes of hundreds of Pseudomonas aeruginosa isolates distributed globally, and heterologous expression of the pathway from P. aeruginosa SCV20265 demonstrated that the product is chemically identical to BCM produced by S. cinnamoneus. Overall, putative BCM gene clusters have been found in at least seven genera spanning Actinobacteria and Proteobacteria (Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria). This represents a rare example of horizontal gene transfer of an intact biosynthetic gene cluster across such distantly related bacteria, and we show that these gene clusters are almost always associated with mobile genetic elements. IMPORTANCE Bicyclomycin is the only natural product antibiotic that selectively inhibits the transcription termination factor Rho. This mechanism of action, combined with its proven biological safety and its activity against clinically relevant Gram-negative bacterial pathogens, makes it a very promising antibiotic candidate. Here, we report the identification of the bicyclomycin biosynthetic gene cluster in the known bicyclomycin-producing organism Streptomyces cinnamoneus, which will enable the engineered production of new bicyclomycin derivatives. The identification of this gene cluster also led to the discovery of hundreds of bicyclomycin pathways encoded in highly diverse bacteria, including in the opportunistic pathogen Pseudomonas aeruginosa. This wide distribution of a complex biosynthetic pathway is very unusual and provides an insight into how a pathway for an antibiotic can be transferred between diverse bacteria.