A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells

Monteiro, Cláudia; Pinheiro, Marina; Fernandes, M. M.; Maia, Sílvia; Seabra, Catarina Leal; Ferreira-da-Silva, Frederico; Reis, Salette; Gomes, Paula; Martins, M. Cristina L.

doi:10.1021/acs.molpharmaceut.5b00113

Cited by 22 publications

(27 citation statements)

References 48 publications

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“…Indeed, in the course of earlier clinical trials where patients were treated either with pexiganan cream or with active oral antibiotics, and compared with the placebo group, pexiganan’s performance proved it to be a possible alternative to oral antibiotics [ 51 ]. These findings triggered several research works focused on pexiganan and related peptides [ 52 , 53 , 54 ], and motivated the patenting of a 0.8% pexiganan acetate cream (Locilex ® , earlier known as Cytolex) in several countries, by the pharmaceutical company Dipexium Pharmaceuticals, Inc. (Houston, TX, USA) in 2016 [ 55 , 56 ]. However, Locilex ® failed approval by the competent international organizations, on the grounds that its efficacy was not proven superior to that of classic oral antibiotics in any of the clinical trials undertaken to date, which include a recent Phase 3 clinical trial promoted by Dipexium, now merged with PLx Pharma, Inc. (Houston, TX, USA) [ 57 ].…”

Section: Wound-healing Antimicrobial Peptidesmentioning

confidence: 99%

Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries

et al. 2017

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As the incidence of diabetes continues to increase in the western world, the prevalence of chronic wounds related to this condition continues to be a major focus of wound care research. Additionally, over 50% of chronic wounds exhibit signs and symptoms that are consistent with localized bacterial biofilms underlying severe infections that contribute to tissue destruction, delayed wound-healing and other serious complications. Most current biomedical approaches for advanced wound care aim at providing antimicrobial protection to the open wound together with a matrix scaffold (often collagen-based) to boost reestablishment of the skin tissue. Therefore, the present review is focused on the efforts that have been made over the past years to find peptides possessing wound-healing properties, towards the development of new and effective wound care treatments for diabetic foot ulcers and other skin and soft tissue infections.

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Section: Wound-healing Antimicrobial Peptidesmentioning

confidence: 99%

Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries

et al. 2017

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“…However, these AMPs also have limitations for commercial and clinical applications such as weak activities, nonspecific cytotoxicity, and poor pharmacokinetic properties. For example, pexiganan (MSI-78) derived from magainin developed as a topical agent failed because it was not superior to other treatment methods [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

Krishnan

Choi

Jang

et al. 2020

IJMS

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Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. Here, we aimed to develop peptide antibiotics with bacterial cell selectivity and potent antibacterial activity against gram-negative bacteria. We designed 10-meric peptides with increased cationicity by adding Arg to the N-terminus of Pro9-3 (Pro10-1) and its D-enantiomeric alteration (Pro10-1D). Among all tested peptides, the newly designed Pro10-1D showed the strongest antibacterial activity against Escherichia coli, Acinetobacter baumannii, and MDR strains with resistance against protease digestion. Pro10-1D can act as a novel potent peptide antibiotic owing to its outstanding inhibitory activities against bacterial film formation with high bacterial cell selectivity. Dye leakage and scanning electron microscopy revealed that Pro10-1D targets the bacterial membrane. Pro10-1D inhibited inflammation via Toll Like Receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) signaling pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Furthermore, Pro10-1D ameliorated multiple-organ damage and attenuated systemic infection-associated inflammation in an E. coli K1-induced sepsis mouse model. Overall, our results suggest that Pro10-1D can potentially serve as a novel peptide antibiotic for the treatment of gram-negative sepsis.

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“…Costa et al and Barbosa et al showed the importance of peptide attachment site in covalent immobilization on antimicrobial activity [14,15,22]. hLF (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) and Dhvar-5 possess a head-to-tail amphipathicity that probably promotes distinctive interactions with bacteria. In this work, we showed that the antimicrobial activity of the α-helical MSI-78(4-20) peptide was not affected by attachment site upon immobilization onto chitosan films, probably due to the distribution of the hydrophobic and hydrophilic amino acids along the sequence.…”

Section: Discussionmentioning

confidence: 99%

AMP–Chitosan Coating with Bactericidal Activity in the Presence of Human Plasma Proteins

et al. 2020

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Antibiotic resistance is increasing and new strategies are needed to fight infection. Advanced materials are promising tools that can be combined with innovative alternatives to conventional antibiotics to allow more targeted and efficient treatment. In this work, we explored the activity against Staphylococcus epidermidis (S. epidermidis) of the α-helical antimicrobial peptide (AMP) MSI-78(4-20) (KFLKKAKKFGKAFVKIL) when covalently bound to a chitosan coating. The AMP MSI-78(4-20) (17 mer) is an improved version of its parent MSI-78 (22 mer; commercially known as Pexiganan), a cost-effective short AMP, which was demonstrated to be as effective as MSI-78 and less toxic to eukaryotic cells. An MSI-78(4-20)–chitosan coating could be applied in several infection scenarios, ranging from bone implants to wound dressings, as chitosan possesses osteoconductive and hemostatic properties. Cysteine-modified MSI-78(4-20) was covalently immobilized onto the chitosan coating through a succinimidyl-[(N-maleimidopropionamido)-octaethyleneglycol] ester (SM(PEG)8), a heterobifuncional crosslinker, with N-hydroxysuccinimide (NHS) ester and maleimide groups, by its N- and C- termini. The MSI-78(4-20)–chitosan coating demonstrated bactericidal properties independently of the tethering site and an improved performance in the presence of plasma proteins, which mimics conditions that will be encountered in vivo. This AMP–chitosan coating has therefore great potential for applications in medical devices such as implants or even wound dressings.

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A 17-mer Membrane-Active MSI-78 Derivative with Improved Selectivity toward Bacterial Cells

Cited by 22 publications

References 48 publications

Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries

Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

AMP–Chitosan Coating with Bactericidal Activity in the Presence of Human Plasma Proteins

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