Antimicrobial metallopeptides with broad nuclease and ribonuclease activity

Joyner, Jeff C.; Hodnick, William F.; Cowan, Ada S.; Tamuly, Deepika; Boyd, R. Vernon; Cowan, J. A.

doi:10.1039/c3cc38977d

Cited by 44 publications

(50 citation statements)

References 29 publications

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“…Each peptide was tested at its MIC (4 and 8 μM for p1 and p3, respectively) and a time when peptide-induced cell death was clearly occurring based on the time-kill curves (30 min for p1 and 4 h for p3). In all of these experiments, Cu 2+ was present at nonantimicrobial concentrations since its MIC on E. coli is > 2 mM [26]. As indicated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cowan and colleagues [25] demonstrated that the noncanonical reactive oxygen species (ROS) directly formed by copper-ATCUN complexes retain the oxidizing power of classical ROS and can damage covalent bonds within minutes. When they added the ATCUN motif to a short synthetic peptide that recognizes bacterial Holliday junctions, they observed significant nuclease activity on isolated DNA and improved minimum inhibitory concentrations (MICs) on planktonic cells [26]. The Angeles-Boza group obtained similar results as well as increased DNA damage in bacterial cells by adding the motif to modified DNA-interacting antimicrobial peptides, such as buforin II [27].…”

Section: Introductionmentioning

confidence: 99%

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Nuclease activity gives an edge to host‐defense peptide piscidin 3 over piscidin 1, rendering it more effective against persisters and biofilms

et al. 2017

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Host-defense peptides (HDPs) feature evolution-tested potency against life-threatening pathogens. While piscidin 1 (p1) and piscidin 3 (p3) are homologous and potent fish HDPs, only p1 is strongly membranolytic. Here, we hypothesize that another mechanism imparts p3 strong potency. We demonstrate that the N-termini of both peptides coordinate Cu and p3-Cu cleaves isolated DNA at a rate on par with free Cu but significantly faster than p1-Cu. On planktonic bacteria, p1 is more antimicrobial but only p3 features copper-dependent DNA cleavage. On biofilms and persister cells, p3-Cu is more active than p1-Cu, commensurate with stronger peptide-induced DNA damage. Molecular dynamics and NMR show that more DNA-peptide interactions exist with p3 than p1, and the peptides adopt conformations simultaneously poised for metal- and DNA-binding. These results generate several important conclusions. First, homologous HDPs cannot be assumed to have identical mechanisms since p1 and p3 eradicate bacteria through distinct relative contributions of membrane and DNA-disruptive effects. Second, the nuclease and membrane activities of p1 and p3 show that naturally occurring HDPs can inflict not only physicochemical but also covalent damage. Third, strong nuclease activity is essential for biofilm and persister cell eradication, as shown by p3, the homolog more specific toward bacteria and more expressed in vascularized tissues. Fourth, p3 combines several physicochemical properties (e.g., Amino Terminal Copper and Nickel binding motif; numerous arginines; moderate hydrophobicity) that confer low membranolytic effects, robust copper-scavenging capability, strong interactions with DNA, and fast nuclease activity. This new knowledge could help design novel therapeutics active against hard-to-treat persister cells and biofilms.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclease activity gives an edge to host‐defense peptide piscidin 3 over piscidin 1, rendering it more effective against persisters and biofilms

et al. 2017

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“…Interestingly, similar nuclease activity has been recently observed and suggested as the main contributor to the increase in antibacterial activity in a metallopeptide containing the GGH motif bound to the DNA-targeting antibacterial sequence WRWYCR. [53,54] …”

Section: Discussionmentioning

confidence: 99%

Improved Bioactivity of Antimicrobial Peptides by Addition of Amino‐Terminal Copper and Nickel (ATCUN) Binding Motifs

2014

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Antimicrobial peptides (AMPs) are promising candidates to help circumvent antibiotic resistance, which is an increasing clinical problem. Amino-terminal copper and nickel (ATCUN) binding motifs are known to actively form reactive oxygen species (ROS) upon metal binding. The combination of these two peptidic constructs could lead to a novel class of dual-acting antimicrobial agents. To test this hypothesis, a set of ATCUN binding motifs were screened for their ability to induce ROS formation, and the most potent were then used to modify AMPs with different modes of action. ATCUN binding motif-containing derivatives of anoplin (GLLKRIKTLL-NH2), pro-apoptotic peptide (PAP; KLAKLAKKLAKLAK-NH2), and sh-buforin (RAGLQFPVGRVHRLLRK-NH2) were synthesized and found to be more active than the parent AMPs against a panel of clinically relevant bacteria. The lower minimum inhibitory concentration (MIC) values for the ATCUN-anoplin peptides are attributed to the higher pore-forming activity along with their ability to cause ROS-induced membrane damage. The addition of the ATCUN motifs to PAP also increases its ability to disrupt membranes. DNA damage is the major contributor to the activity of the ATCUN-sh-buforin peptides. Our findings indicate that the addition of ATCUN motifs to AMPs is a simple strategy that leads to AMPs with higher antibacterial activity and possibly to more potent, usable antibacterial agents.

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“…Nucleic acids are more susceptible to hydrolysis and much of the work in this area has focused on artificial nucleases that cleave the phosphodiester bond, as exemplified by work from Morrow and Richards and coworkers [62]. There is still precedence, however for the oxidative cleavage of nucleic acids and, in fact, many of the catalytic metallodrugs that incorporate the ATCUN motif react via oxidation of DNA [59]; this nuclease activity has been implicated in the mechanism of antimicrobial peptides [82]. The texaphyrins pioneered in the Sessler lab also act through reactive oxygen species (ROS) that react with DNA and lead to cell death [83].…”

Section: His103mentioning

confidence: 97%

From Traditional Drug Design to Catalytic Metallodrugs: A Brief History of the Use of Metals in Medicine

Bradford¹,

Cowan²

2014

Metallodrugs

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Traditional drug design has been effective in the development of therapies for a variety of disease states but there is a need for new approaches that will tackle new challenges and complement current paradigms. The use of metals in medicine has resulted in several successes and allows for the introduction of properties that cannot be achieved by use of organic compounds alone, but also introduces new challenges that can be addressed by a careful understanding of the principles of inorganic chemistry. Toward this end, the unique structural and coordination chemistry, as well as the reactivity of metals, has been used to design novel classes of therapeutic and diagnostic agents. This review briefly summarizes progress in the field of therapeutics, from the earliest use of metals to more recent efforts to design catalytic metallodrugs that promote the irreversible inactivation of therapeutically relevant targets.

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Antimicrobial metallopeptides with broad nuclease and ribonuclease activity

Cited by 44 publications

References 29 publications

Nuclease activity gives an edge to host‐defense peptide piscidin 3 over piscidin 1, rendering it more effective against persisters and biofilms

Nuclease activity gives an edge to host‐defense peptide piscidin 3 over piscidin 1, rendering it more effective against persisters and biofilms

Improved Bioactivity of Antimicrobial Peptides by Addition of Amino‐Terminal Copper and Nickel (ATCUN) Binding Motifs

From Traditional Drug Design to Catalytic Metallodrugs: A Brief History of the Use of Metals in Medicine

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