Highly Potent Antibacterial Organometallic Peptide Conjugates

Abstract

Resistance of pathogenic bacteria against currently marketed antibiotics is again increasing. To meet the societal need for effective cures, scientists are faced with the challenge of developing more potent but equally bacteria-specific drugs. Currently, most efforts are directed toward the modification of existing antibiotics, but ideally, compounds with a new mode of action are required. In this Account, we detail our findings in the area of novel metal-based antibiotics. Our strategy is based on the modification of simple antimicrobial peptides (AMPs) with organometallic agents, resulting in organometallic AMPs (OM-AMPs). Since bacteria have most likely never encountered these synthetically prepared unnatural organometallic agents, we anticipated that such agents could well become potentiating players in the antibiotics arena. Moreover, exploiting some of the particular properties of metal complexes should also help to elucidate the mode of action of small cationic AMPs, the molecular details of which have remained elusive despite intensive efforts. Using standard Fmoc/tBu-based solid-phase peptide synthesis approaches, we have prepared various organometallic-peptide conjugates with covalently linked group 8 and 9 metallocenes (ferrocene, ruthenocene, osmocene, and cobaltocenium). As a starting point we took the (RW) antibacterial hexapeptide lead structure. After modifying the peptide sequence (generations 1 and 2), changing the nature and position of the organometallic group (generation 3), and optimizing the amino acid chirality (generation 5), we identified several organometallic antibacterial peptides that are currently among the most active synthetic AMPs (synAMPs) that have ever been prepared. Through these rational and systematic optimizations, we were able to increase the antibacterial activity of a short non-organometallic synAMP 18-fold to submicromolar activity, rivaling the activity of vancomycin (often the drug of last resort) against methicillin-resistant Staphylococcus aureus (MRSA). Moreover, by making use of the unique physicochemical properties of ruthenocene, we were able to determine the mode of action of these short AMPs in unprecedented detail. We propose that the OM-AMP integrates into the bacterial membrane and changes its biophysical properties, which ultimately results in detachment of vital enzymes for respiration and cell-wall biosynthesis such as specifically cytochrome c and MurG from their locations in the membrane. Further explorations of these small OM-AMP derivatives that are summarized in this Account include lipid substitution, multivalent display of metalated di- or tripeptides on a trivalent scaffold with different linkers, and increasing the metal-to-peptide ratio such that every tryptophan in the (RW) scaffold is eventually replaced by a metalated lysine. While initial experiments with our OM-AMPs for systemic applications were largely disappointing, these OM-AMPs turned out to be potent antibiotics for topical applications. In this sense, two applications are described...

Cation‐Anion Redox Switching in an All‐Ferrocene Salt

“…Investigations into ferrocene compounds as redox active materials continue to grow . Recently, attention has turned to the use of ferrocenes as possible components in redox flow battery (RFB) applications, arising from the desire to produce new chemical compounds for the low cost and scalable storage of energy.…”

“…Investigations into ferrocene compounds as redox active materials continue to grow. [1][2][3][4][5][6][7][8] Recently, attention has turned to the use of ferrocenes as possible components in redox flow battery (RFB) applications, [9][10][11][12][13][14][15][16][17][18][19] arising from the desire to produce new chemical compounds for the low cost and scalable storage of energy. Among transition metal-based compounds, ferrocenes have many notable properties as RFB components, ranging from their relative low cost and ease of synthesis to their stabilities and electrochemical reversibility in a variety of media.…”

Palladium(II)‐Catalyzed Enantioselective C−H Alkenylation of Ferrocenecarboxylic Acid

“…However, ferrocenyl carboxylic acid as starting material has rarely been studied . Due to ferrocenecarboxylic acid with excellent redox properties and widely used in electrochemical, redox probes, and peptide chain modifications, and with antibacterial, antineoplastic and anticancer activities, and our ongoing efforts to build clean C−H bond functionalizations, we herein explore Pd(II)‐catalyzed enantioselective C−H alkenylation of ferrocenecarboxylic acid using chiral amino acid as ligand, oxygen as an oxidant. A series of 2‐alkenylferrocene carboxylic acids with planar chirality were obtained under mild reaction conditions.…”

Synthesis, reactivity and preliminary biological activity of iron(0) complexes with cyclopentadienone and amino‐appended N‐heterocyclic carbene ligands

“…One area that has certainly received a significant attention is the application of coordination and organometallic complexes as drugs or prodrugs in the cancer treatment . The readily available and inexpensive iron is a good candidate as a key component in many important biological processes, and ferrocene derivatives are among the most studied iron complexes for their bio‐inorganic properties related to their reactivity and electrochemical properties . Mechanistic studies of ferrocifens highlighted cytostatic properties on tumors, thus causing death of cells by senescence.…”

“…[4][5][6][7][8][9][10][11] The readily available and inexpensive iron is a good candidate as a key component in many important biological processes, [12] and ferrocene derivatives are among the most studied iron complexes for their bioinorganic properties related to their reactivity and electrochemical properties. [13][14][15][16][17][18][19] Mechanistic studies of ferrocifens highlighted cytostatic properties on tumors, thus causing death of cells by senescence. The presence of side-chain amino groups on ferrocifen complexes leads to major toxicity, [19] similar to the one observed with other metallocenes.…”