Towards eco-friendly marine antifouling biocides – Nature inspired tetrasubstituted 2,5-diketopiperazines

Grant, Thomas M.; Rennison, David; Cervin, Gunnar; Pavia, Henrik; Hellio, Claire; Foulon, Valentin; Brimble, Margaret A.; Cahill, Patrick; Svenson, Johan

doi:10.1016/j.scitotenv.2021.152487

Cited by 20 publications

(49 citation statements)

References 70 publications

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“…2,5 diketopiperazines (DKPs) are cyclic dipeptides and are regarded as privileged structures with the ability to bind to a range of natural receptors (90). 2,5-DKPs present a near ideal scaffold for the development of novel antimicrobial compounds, as they are chemically accessible, highly stable, and amenable to extensive synthetic derivatisation at up to six positions to develop versatile bioactive compounds (69,91,92). In addition to freedom in terms of amino acid stereochemistry and choice of sidechains, up to four additional substituents can be further incorporated via different alkylation strategies (90,91).…”

Section: 5-diketopiperazinesmentioning

confidence: 99%

“…The exact mode of action is expected to depend on the sequence/structure and target species and are often not reported in detail beyond illustrating membrane insertion or disruption (93,166). Selected mimics have been shown to be active also against marine microorganisms which further suggest multiple modes of action given the spread in cell surface and membrane composition (6,69,167).…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

“…Adding more hydrophobic residues usually increases the antimicrobial activity but also at a cost of lowered cellular selectivity (63,64,82). Adding too much hydrophobicity renders the compounds inactive, either due to aggregation or poor solubility and has been seen in several studies (69,149,172). The optimal balance between charge and hydrophobicity differs depending on scaffold studied and it has not been quantified much further than the 2 + 2 pharmacophore for the compounds covered in this review.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

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Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

2022

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The search for efficient antimicrobial therapies that can alleviate suffering caused by infections from resistant bacteria is more urgent than ever before. Infections caused by multi-resistant pathogens represent a significant and increasing burden to healthcare and society and researcher are investigating new classes of bioactive compounds to slow down this development. Antimicrobial peptides from the innate immune system represent one promising class that offers a potential solution to the antibiotic resistance problem due to their mode of action on the microbial membranes. However, challenges associated with pharmacokinetics, bioavailability and off-target toxicity are slowing down the advancement and use of innate defensive peptides. Improving the therapeutic properties of these peptides is a strategy for reducing the clinical limitations and synthetic mimics of antimicrobial peptides are emerging as a promising class of molecules for a variety of antimicrobial applications. These compounds can be made significantly shorter while maintaining, or even improving antimicrobial properties, and several downsized synthetic mimics are now in clinical development for a range of infectious diseases. A variety of strategies can be employed to prepare these small compounds and this review describes the different compounds developed to date by adhering to a minimum pharmacophore based on an amphiphilic balance between cationic charge and hydrophobicity. These compounds can be made as small as dipeptides, circumventing the need for large compounds with elaborate three-dimensional structures to generate simplified and potent antimicrobial mimics for a range of medical applications. This review highlight key and recent development in the field of small antimicrobial peptide mimics as a promising class of antimicrobials, illustrating just how small you can go.

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Section: 5-diketopiperazinesmentioning

confidence: 99%

Section: Structure-activity Relationshipmentioning

confidence: 99%

Section: Structure-activity Relationshipmentioning

confidence: 99%

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Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

2022

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“…Despite the promising activity of cAMPs, developing them as drug candidates is a major challenge due to their inherent instability to enzymatic degradation, which results in short pharmacokinetic half-lives and low oral bioavailability. ,− The incorporation of unnatural amino acids has been successfully employed to increase the potency and prolong the half-lives of cAMPs, and recent research has expanded to other more stable backbone scaffolds. − 2,5-Diketopiperazines (DKPs) present an ideal scaffold from which to build novel antimicrobial compounds, as they are chemically accessible, highly stable, and amenable to extensive synthetic derivatization at several positions. − 2,5-DKPs are cyclic dipeptides that exist in a planar, chair, pseudoboat, or twist form, with a small energy gap between the conformers (1.3–1.7 kcal/mol) that varies depending on the ring substituents. , …”

mentioning

confidence: 99%

Stereochemical Effects on the Antimicrobial Properties of Tetrasubstituted 2,5-Diketopiperazines

Grant

Rennison

Mros

et al. 2022

ACS Med. Chem. Lett.

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Antimicrobial drug resistance is a looming health crisis facing us in the modern era, and new drugs are urgently needed to combat this growing problem. Synthetic mimics of antimicrobial peptides have recently emerged as a promising class of compounds for the treatment of persistent microbial infections. In the current study, we investigate five cyclic N-alkylated amphiphilic 2,5-diketopiperazines against 15 different strains of bacteria and fungi, including drug-resistant clinical isolates. Several of the 2,5-diketopiperazines displayed activities similar or superior to antibiotics currently in clinical use, with activities coupled to both the cationic and hydrophobic substituents. All possible stereoisomers of the lead peptide were prepared, and the effects of stereochemistry and amphiphilicity were investigated via 1D and 2D NMR spectroscopy, solution dynamics, and membrane interaction modeling. Clear differences in solution structures and membrane interaction potentials explain the differences seen in the bioactivity and physicochemical properties of each stereoisomer.

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“…Antifouling activity was assessed via inhibition of settlement and metamorphosis of larvae of the Pacific transparent sea squirt ( Ciona savignyi ) and the blue mussel ( Mytilus galloprovincialis ). Methods followed those published by Grant et al [ 81 ]. Adults of both species were collected from coastal populations in the Nelson region of New Zealand, held in a recirculating seawater system (18 ± 1 °C, 33 ± 1 PSU) and fed bulk-cultured Isochorysis galbana until ready to spawn.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Ircinianin Lactones B and C—Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii

et al. 2022

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Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C (7 and 8), together with five known entities from the ircinianin compound family (1, 3–6) were isolated from the marine sponge Ircinia wistarii. Ircinianin lactones B and C (7 and 8) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations. In a broad screening approach for biological activity, the class-defining compound ircinianin (1) showed moderate antiprotozoal activity against Plasmodium falciparum (IC50 25.4 μM) and Leishmania donovani (IC50 16.6 μM).

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Towards eco-friendly marine antifouling biocides – Nature inspired tetrasubstituted 2,5-diketopiperazines

Cited by 20 publications

References 70 publications

Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter?

Stereochemical Effects on the Antimicrobial Properties of Tetrasubstituted 2,5-Diketopiperazines

Discovery of Ircinianin Lactones B and C—Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii

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