Dinarvand Mojdeh, Spain Malcolm
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Department of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
Antibiotics (Basel). 2021 Mar 22;10(3):337. doi: 10.3390/antibiotics10030337.
Marine natural products (MNPs) have been an important and rich source for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein, we report bioassay guided fractionation of marine extracts from sponges , and that led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: aniline , benzylamine , tertiary amine and , and quaternary amine salt , along with three known compounds () were isolated from a crude extract and MeOH eluent marine extracts. The antibiotic activities of the compounds, and their isolation as natural products have not been reported before. Using tandem mass spectrometry (MS) analysis, potential structures of the bioactive fractions were assigned, leading to the hit validation of potential compounds through synthesis, and commercially available compounds. This method is a novel strategy to overcome insufficient quantities of pure material (NPs) for drug discovery and development which is a big challenge for pharmaceutical companies. The antibacterial screening of the marine extracts has shown several of the compounds exhibited potent in-vitro antibacterial activity, especially against methicillin-resistant (MRSA) with minimum inhibitory concentration (MIC) values between 15.6 to 62.5 microg mL. Herein, we also report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure-activity relationships (SAR) results demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity. Several commercially available compounds, which are structurally related to the discovered molecules, showed broad-spectrum antimicrobial activity against different test pathogens with a MIC range of 50 to 0.01 µM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds have increased bioactivity.
海洋天然产物一直是抗菌药物发现的重要且丰富的来源，也是控制耐药性感染的有效替代方法。在此，我们报告了对海绵海洋提取物进行生物测定指导的分级分离，这使我们鉴定出了具有抗菌特性的新型化合物。从粗提物和甲醇洗脱的海洋提取物中分离出叔胺或季铵盐：苯胺、苄胺、叔胺以及季铵盐，以及三种已知化合物（）。这些化合物的抗生素活性及其作为天然产物的分离此前尚未见报道。通过串联质谱（MS）分析，确定了生物活性组分的潜在结构，从而通过合成以及市售化合物对潜在化合物进行了命中验证。该方法是一种新颖的策略，可克服药物发现和开发中纯物质（天然产物）数量不足的问题，这对制药公司来说是一个巨大的挑战。海洋提取物的抗菌筛选表明，其中几种化合物表现出强大的体外抗菌活性，尤其是对耐甲氧西林金黄色葡萄球菌（MRSA），其最低抑菌浓度（MIC）值在15.6至62.5微克/毫升之间。在此，我们还报告了一系列结构相似的市售化合物的构效关系。构效关系（SAR）结果表明，通过线性链长修饰胺以及引入芳香环会改变观察到的抗菌活性。几种与所发现分子结构相关的市售化合物对不同测试病原体表现出广谱抗菌活性，MIC范围为50至0.01微摩尔。抗菌活性和细胞毒性交叉参考的结果表明，这些化合物是有前景的潜在分子，具有有利于抗菌药物开发的治疗指数。此外SAR研究表明，分离化合物的简化类似物具有更高的生物活性。
