title: Analysis of the mechanism of action of potent antibacterial hetero-tri-organometallic compounds: a structurally new class of antibiotics.
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.
authors.affiliation: Biology of Microorganisms and ‡Bioinorganic Chemistry, Ruhr University Bochum , Bochum, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wenzel
authors.forename: Malay
authors.initials: M
authors.lastname: Patra
authors.forename: Christoph Helmut Rudi
authors.initials: CH
authors.lastname: Senges
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Jennifer Janina
authors.initials: JJ
authors.lastname: Stepanek
authors.forename: Antonio
authors.initials: A
authors.lastname: Pinto
authors.forename: Pascal
authors.initials: P
authors.lastname: Prochnow
authors.forename: Cuong
authors.initials: C
authors.lastname: Vuong
authors.forename: Sina
authors.initials: S
authors.lastname: Langklotz
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
authors.forename: Julia Elisabeth
authors.initials: JE
authors.lastname: Bandow
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D020135:Peptide Nucleic Acids / Q000737:chemistry / Q000494:pharmacology; D040901:Proteomics; D013054:Spectrophotometry, Atomic
chemical_list: D000900:Anti-Bacterial Agents; D009942:Organometallic Compounds; D020135:Peptide Nucleic Acids