Patra Malay, Wenzel Michaela, Prochnow Pascal, Pierroz Vanessa, Gasser Gilles, Bandow Julia E, Metzler-Nolte Nils
Lehrstuhl für Anorganische Chemie I - Bioanorganische Chemie , Fakultät für Chemie und Biochemie , Ruhr-Universität Bochum , Universitätsstrasse 150 , D-44801 Bochum , Germany . Email:
Ruhr-Universität Bochum , Biologie der Mikroorganismen , Arbeitsgruppe Mikrobielle Antibiotikaforschung , Universitätsstrasse 150 , D-44801 Bochum , Germany . Email:
Chem Sci. 2015 Jan 1;6(1):214-224. doi: 10.1039/c4sc02709d. Epub 2014 Oct 13.
The worrying appearance of microbial resistance to antibiotics is a worldwide problem which needs to be tackled urgently. Microbial resistance to the common classes of antibiotics involving purely organic compounds unfortunately develops very rapidly and in most cases, resistance was detected soon after or even before release of the antibiotic to the market. Therefore, novel concepts for antibiotics must be investigated, and metal-containing compounds hold particular promise in that area. Taking a trimetallic complex () which contains a ferrocenyl (Fc), a CpMn(CO) (cymantrene) and a [(dpa)Re(CO)] residue as the lead structure, a systematic structure-activity relationship (SAR) study against various gram-positive pathogenic bacteria including methicillin-resistant (MRSA) strains was performed. The [(dpa)Re(CO)] moiety was discovered to be the essential unit for the observed antibacterial activity of . The ferrocenyl and CpMn(CO) units can be replaced one by one or both together by organic moieties such as a phenyl ring without loss of antibacterial activity. The most potent mono-metallic complex () has an antibacterial activity comparable to the well-established organic drugs amoxicillin and norfloxacin and importantly, only moderate cytotoxicity against mammalian cells. Microbiological studies on membrane potential, membrane permeabilization, and cell wall integrity revealed that targets the bacterial membrane and disturbs cell wall integrity, but shows more efficient membrane permeabilization than the lead structure .
微生物对抗生素产生耐药性这一令人担忧的现象是一个全球性问题，亟待解决。不幸的是，微生物对涉及纯有机化合物的常见抗生素类别产生耐药性的速度非常快，而且在大多数情况下，在抗生素投放市场后不久甚至之前就检测到了耐药性。因此，必须研究抗生素的新观念，而含金属化合物在该领域具有特别的前景。以一种含有二茂铁基（Fc）、茂基锰（羰基）（环戊二烯基锰羰基化合物）和[(二吡啶胺)铼(羰基)]残基的三金属配合物（）作为先导结构，针对包括耐甲氧西林金黄色葡萄球菌（MRSA）菌株在内的各种革兰氏阳性病原菌进行了系统的构效关系（SAR）研究。发现[(二吡啶胺)铼(羰基)]部分是观察到的的抗菌活性的关键单元。二茂铁基和茂基锰（羰基）单元可以逐个或一起被诸如苯环等有机部分取代，而不会丧失抗菌活性。最有效的单金属配合物（）具有与成熟的有机药物阿莫西林和诺氟沙星相当的抗菌活性，重要 的是，对哺乳动物细胞只有适度的细胞毒性。关于膜电位、膜通透性和细胞壁完整性的微生物学研究表明，靶向细菌膜并扰乱细胞壁完整性，但比先导结构表现出更有效的膜通透性。
