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ACS Chem Biol. 2013 Jul 19;8(7):1442-50. doi: 10.1021/cb4000844. Epub 2013 Apr 26.

Analysis of the mechanism of action of potent antibacterial hetero-tri-organometallic compounds: a structurally new class of antibiotics.

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1
Biology of Microorganisms and ‡Bioinorganic Chemistry, Ruhr University Bochum , Bochum, Germany.

Abstract

Two hetero-tri-organometallic compounds with potent activity against Gram-positive bacteria including multi-resistant Staphylococcus aureus (MRSA) were identified. The compounds consist of a peptide nucleic acid backbone with an alkyne side chain, substituted with a cymantrene, a (dipicolyl)Re(CO)3 moiety, and either a ferrocene (FcPNA) or a ruthenocene (RcPNA). Comparative proteomic analysis indicates the bacterial membrane as antibiotic target structure. FcPNA accumulation in the membrane was confirmed by manganese tracing with atomic absorption spectroscopy. Both organometallics disturbed several essential cellular processes taking place at the membrane such as respiration and cell wall biosynthesis, suggesting that the compounds affect membrane architecture. Correlating with enhanced antibacterial activity, oxidative stress was induced only by the ferrocene-substituted compound. The organometallics described here target the cytoplasmic membrane, a clinically proven antibacterial target structure, feature a bactericidal but non-bacteriolytic mode of action and limited cytotoxicity within the limits of solubility. Thus, FcPNA represents a promising lead structure for the development of a new synthetic class of antibiotics.

PMID:
23578171
DOI:
10.1021/cb4000844
[Indexed for MEDLINE]

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