Department of Chemistry, Fribourg University, Chemin Du Musée 9, 1700, Fribourg, Switzerland.
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042, Belgrade, Serbia.
Eur J Med Chem. 2021 Dec 15;226:113858. doi: 10.1016/j.ejmech.2021.113858. Epub 2021 Sep 20.
Antimicrobial resistance (AMR) is a major emerging threat to public health, causing serious issues in the successful prevention and treatment of persistent diseases. While the problem escalates, lack of financial incentive has lead major pharmaceutical companies to interrupt their antibiotic drug discovery programs. The World Health Organisation (WHO) has called for novel solutions outside the traditional development pathway, with emphasis on new classes of active compounds with non-classical mechanisms of action. Metal complexes are an untapped source of antibiotic potential owing to unique modes of action and a wider range of three-dimensional geometries as compared to purely organic compounds. In this study, we present the antimicrobial and antifungal efficacy of a family of rhenium tricarbonyl diimine complexes with varying ligands, charge and lipophilicity. Our study allowed the identification of potent and non-toxic complexes active in vivo against S. aureus infections at MIC doses as low as 300 ng/mL, as well as against C. albicans-MRSA mixed co-infection. The compounds are capable of suppressing the C. albicans morphogenetic yeast-to-hyphal transition, eradicating fungal-S. aureus co-infection, while showing no sign of cardio-, hepato-, hematotoxiciy or teratogenicity.
抗微生物药物耐药性（AMR）是对公众健康的主要新兴威胁，导致持续疾病的成功预防和治疗出现严重问题。随着问题的升级，缺乏财政激励促使主要制药公司中断了抗生素药物发现计划。世界卫生组织（WHO）呼吁在传统开发途径之外寻求新的解决方案，重点是具有非经典作用机制的新型活性化合物类别。与纯有机化合物相比，金属配合物具有独特的作用模式和更广泛的三维几何形状，是抗生素潜力的未开发来源。在这项研究中，我们提出了一系列具有不同配体、电荷和亲脂性的铼三羰基二亚胺配合物的抗微生物和抗真菌功效。我们的研究确定了具有效力且无毒的复合物，它们在体内对金黄色葡萄球菌感染的 MIC 剂量低至 300ng/mL 时具有活性，并且对白色念珠菌-MRSA 混合感染也具有活性。这些化合物能够抑制白色念珠菌形态发生的酵母到菌丝的转变，根除真菌-金黄色葡萄球菌的混合感染，同时没有心脏、肝脏、血液毒性或致畸性的迹象。
