Structure and antibacterial activities of new cyclic peptide antibiotics, pargamicins B, C and D, from Amycolatopsis sp ML1-hF4
Structure and antibacterial activities of new cyclic peptide antibiotics, pargamicins B, C and D, from Amycolatopsis sp ML1-hF4
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DOI：
10.1038/ja.2017.34
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发表时间：
2017-05-01
影响因子：
3.3
通讯作者：
Igarashi, Masayuki
中科院分区：
文献类型：
--
作者：
Hashizume, Hideki;Sawa, Ryuichi;Igarashi, Masayuki
正如CDC 1和世界卫生组织所警告的那样，由耐药细菌引起的传染病是目前医疗领域面临的最严重问题之一。2、3在这些耐药菌中，耐甲氧西林金黄色葡萄球菌和耐万古霉素粪肠球菌(VRE)是两种最难治的医院内广谱耐药病原菌。万古霉素一直被用作治疗金黄色葡萄球菌和肠球菌引起的传染病的最后手段；然而，自1986年以来，VRE菌株出现并广泛传播。4、5本世纪初以来，已有6株和33株高水平耐万古霉素金黄色葡萄球菌出现在亚洲国家和美国。在筛选对耐甲氧西林金黄色葡萄球菌和VRE都有活性的抗生素的过程中，从土壤放线菌菌株Amycolatopsis sp.的发酵液中发现了帕伽米星A(PRG-A，图1)。ML1-hF4。8-PRG-A是一种结构独特的环肽，由N-甲基-3-羟基缬氨酸、4-羟基哌酸(4-OH-PIP)、肌氨酸、苯丙氨酸、N-羟基异亮氨酸(NoH-Ile)和哌齐酸(Pip)组成，具有良好的体外抗菌活性，可与包括万古霉素在内的其他现有药物相媲美或更强。8我们以前的研究表明，PRG-A通过破坏靶细胞膜完整性的机制对葡萄球菌和肠球菌发挥快速杀菌活性，9这是一种与达托霉素不同的作用模式。9，10在PRG-A生产的优化过程中，我们在PRG-A产生菌的发酵液中发现了新的活性成分PRG-B、-C和-D(图1)。ML1-hF4。本研究对这些新的PRG-A类似物的发酵、分离、结构鉴定和抗菌活性进行了研究，并对其构效关系进行了探讨。
Infectious diseases caused by drug-resistant bacteria are one of the most serious problems currently facing the medical field, as warned by the CDC 1 and the WHO. 2, 3 Among these drug-resistant bacteria, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis/faecium (VRE) are two of the most intractable nosocomial pathogens that show broad-range drug resistance. Vancomycin has been used as the last resort for the treatment of infectious diseases caused by S. aureus and enterococci; however, since 1986, VRE strains have emerged and become widespread. 4, 5 Since the beginning of this century, vancomycin intermediate-resistant S. aureus have been frequently isolated 6 and 33 strains of vancomycin high-level resistant S. aureus have also emerged in Asian countries and in the United States. 7 Effective drugs against these pathogens are urgently needed.During the course of our screening for antibiotics active against both methicillin-resistant S. aureus and VRE, pargamicin A (PRG-A, Figure 1) was discovered from the fermentation broth of soil actinomycete strain Amycolatopsis sp. ML1-hF4. 8 PRG-A is a structurally unique cyclic peptide consisting of N-methyl-3-hydroxy valine, 4-hydroxy piperazic acid (4-OH-Pip), sarcosine, phenylalanine, N-hydroxy isoleucine (NOH-Ile) and piperazic acid (Pip), which shows excellent in vitro antibacterial activity that is either comparable to, or more potent than, that of other currently available drugs, including vancomycin. 8 Our previous studies revealed that PRG-A exerted rapid bactericidal activity against staphylococci and enterococci via a mechanism that involved disruption of the membrane integrity of the target cells, 9 a mode of action distinct from that of daptomycin. 9, 10 During the process of optimization of PRG-A production, we discovered new active components PRG-B,-C and-D (Figure 1) in the culture broth of the PRG-A-producing strain Amycolatopsis sp. ML1-hF4. This present study investigates the fermentation, isolation, structural elucidation and antimicrobial activities of these new PRG-A-analogs and discusses the structure–activity relationship of PRGs.