Frei Angelo, Zuegg Johannes, Elliott Alysha G, Baker Murray, Braese Stefan, Brown Christopher, Chen Feng, G Dowson Christopher, Dujardin Gilles, Jung Nicole, King A Paden, Mansour Ahmed M, Massi Massimiliano, Moat John, Mohamed Heba A, Renfrew Anna K, Rutledge Peter J, Sadler Peter J, Todd Matthew H, Willans Charlotte E, Wilson Justin J, Cooper Matthew A, Blaskovich Mark A T
Centre for Superbug Solutions , Institute for Molecular Bioscience , The University of Queensland , St. Lucia , Queensland 4072 , Australia . Email:
School of Molecular Sciences , The University of Western Australia , Stirling Highway , 6009 Perth , Australia.
Chem Sci. 2020 Feb 12;11(10):2627-2639. doi: 10.1039/c9sc06460e. eCollection 2020 Mar 14.
There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
迫切需要新的抗菌化合物来应对广泛存在的抗生素耐药性这一日益严重的威胁。目前可用的药物研发渠道非常有限，主要由已知抗生素的衍生物组成，因此迫切需要新型抗生素。金属配合物目前正处于治疗癌症、疟疾和神经退行性疾病的临床开发阶段。然而，它们作为潜在抗菌化合物的应用却很少受到关注。我们报告了对906种含金属化合物的评估，这些化合物已由开放抗菌药物发现社区（CO-ADD）筛选其抗菌活性。与CO-ADD数据库中的纯有机分子（0.87%）相比，含金属化合物的命中率显著更高（9.9%）。在906种化合物中，有88种对至少一种测试菌株（包括真菌）具有活性，同时对哺乳动物细胞系没有任何细胞毒性或溶血特性。在此，我们重点介绍了30种对革兰氏阳性和/或革兰氏阴性细菌具有活性的化合物的结构，这些化合物含有锰、钴、锌、钌、银、铕、铱和铂，对耐甲氧西林金黄色葡萄球菌（MRSA）的活性低至纳摩尔范围。其中23种配合物以前尚未报道过其抗菌特性。这项工作揭示了含金属化合物可为抗菌研究带来的巨大多样性。提高对这类化合物的认识对于设计具有对抗抗菌耐药性潜力的真正新型抗生素非常重要。
