针对“超级细菌”研发 抗耐药菌活性天然产物研究取得突破

toto

Functional Analysis of Cytochrome P450s Involved in Streptovaricin Biosynthesis and Generation of Anti-MRSA AnaloguesThe streptovaricins, chemically related to the rifamycins, are highly effective antibacterial agents, particularly against mycobacteria. Herein, a bioassay-guided investigation of Streptomyces spectabilis CCTCC M2017417 has led to the characterization of streptovaricins as potent compounds against methicillin-resistant Staphylococcus aureus (MRSA). We identified the streptovaricin biosynthetic gene cluster from S. spectabilis CCTCC M2017417 based on genomic sequencing and bioinformatic analysis. Targeted in-frame deletion of five cytochrome P450 genes (stvP1–P5) resulted in the identification of four new streptovaricin analogues and revealed the functions of these genes as follows: stvP1, stvP4, and stvP5 are responsible for the hydroxylation of C-20, Me-24, and C-28, respectively. stvP2 is possibly involved in formation of the methylenedioxy bridge, and stvP3, a conserved gene found in the biosynthetic cluster for naphthalenic ansamycins, might be related to the formation of a naphthalene ring. Biochemical verification of the hydroxylase activity of StvP1, StvP4, and StvP5 was performed, and StvP1 showed unexpected biocatalytic specificity and promiscuity. More importantly, anti-MRSA studies of streptovaricins and derivatives revealed significant structure–activity relationships (SARs): The hydroxyl group at C-28 plays a vital role in antibacterial activity. The hydroxyl group at C-20 substantially enhances activity in the absence of the methoxycarbonyl side chain at C-24, which can increase the activity regardless of the presence of a hydroxyl group at C-20. The inner lactone ring between C-21 and C-24 shows a positive effect on activity. This work provides meaningful information on the SARs of streptovaricins and demonstrates the utility of the engineering of streptovaricins to yield novel anti-MRSA molecules.

szliuyan2e

所谓道高一尺魔高一丈，抗生素研究始终跟不上细菌耐药的演变，天然活性产物的研究也许才会带来希望

ynosmile

战胜超级细菌，减少疾病传播，保障医患安全，健康快乐生活。

lyluoxiuhua

防控多重耐药菌感染任务艰巨，我们尚需继续努力！

荷儿

英文不好，有道词典翻译了一下，也不知道意思表达是否确切。发上来让英文好的老师们纠错，让和我一样英文不好的老师们看懂
“对链霉素的生物合成和抗mrsa模拟产生的细胞色素P450s的功能分析，与利福霉素的化学相关，是高效的抗菌药物，特别是对分枝杆菌。在此，一项对链霉素的生物化学引导的研究，将链霉素的特性描述为对耐甲氧西林金黄色葡萄球菌(MRSA)的有效成分。基于基因组测序和生物信息学分析，从s . spectabilis CCTCC M2017417中发现了链球菌生物合成基因。对5个细胞色素P450基因(stvP1 - p5)进行帧内删除后，发现4种新的链霉素类似物，并揭示了这些基因的功能:stvP1、stvP4和stvP5分别负责c - 20、me - 24和c - 28的羟基化。stvP2可能参与了甲乙二氧基桥的形成，而stvP3，是一种在萘霉素生物合成簇中发现的保守基因，可能与萘环的形成有关。对StvP1、StvP4、StvP5的羟酶活性进行了生化验证，StvP1表现出了意想不到的生物特异性和滥交性。更重要的是，对链球菌和衍生物的抗mrsa研究揭示了重要的结构-活性关系(SARs):c - 28的羟基组在抗菌活性中起着至关重要的作用。c - 20的羟羰基在c - 24中没有甲基羰基侧链，从而大大提高了活性，无论c - 20的羟基是否存在，都可以增加活性。c - 21与c - 24之间的内酯环对活性有积极作用。本研究提供了有意义的关于链球菌SARs的信息，并展示了链状静脉曲张的工程效用，以产生新型的抗mrsa分子。”