Development of an insect metalloproteinase inhibitor drug carrier system for application in chronic wound infections

Eisenhardt, Michaela; Dobler, Dorota; Schlupp, Peggy; Schmidts, Thomas; Salzig, Mark; Vilcinskas, Andreas; Salzig, Denise; Czermak, Peter; Keusgen, Michael; Runkel, Frank

doi:10.1111/jphp.12452

Cited by 9 publications

(9 citation statements)

References 53 publications

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“…[2,5] We found that IMPI, a metalloprotease inhibitor from G. mellonella, inhibits an important P. aeruginosa virulence factor, the metalloproteinase PE, [1] as well as other M4 metalloproteases. [28,29,31,36] A GST fusion tag does not affect the activity of native IMPI, [32] allowing us to produce a functional recombinant IMPI fusion protein in E. coli which showed a stable and batch-independent ability to inhibit thermolysin and purified PE, with a steeper descent than that of the chemical inhibitor phosphoramidon (Figure 1). IMPI is more specific and more potent than other PE-inhibitors [28] such as those based on hydroxamate, [37] metal-chelating dipeptides, [38][39][40] or small molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Given the potential of IMPI for the treatment of P. aeruginosa infections, we produced a recombinant insect metalloproteinase inhibitor‐glutathione‐S‐transferase (IMPI‐GST) fusion protein in Escherichia coli and tested its ability to inhibit the M4 metalloproteinases thermolysin and PE, as well as the P. aeruginosa secretome (Sec). We investigated the influence of Sec on skin cells and in vitro and ex vivo porcine wound models using a thermosensitive hydrogel for IMPI application . Finally, we tested the ability of IMPI‐GST to restore the viability and migration capacity of Sec‐treated keratinocytes and to prevent necrosis in a porcine wound model.…”

Section: Introductionmentioning

confidence: 99%

“…We investigated the influence of Sec on skin cells and in vitro and ex vivo porcine wound models using a thermosensitive hydrogel for IMPI application. [32] Finally, we tested the ability of IMPI-GST to restore the viability and migration capacity of Sec-treated keratinocytes and to prevent necrosis in a porcine wound model.…”

Section: Introductionmentioning

confidence: 99%

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The therapeutic potential of the insect metalloproteinase inhibitor against infections caused by Pseudomonas aeruginosa

Eisenhardt

Schlupp

Höfer

et al. 2018

Journal of Pharmacy and Pharmacology

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Objectives The objective of this study was to investigate the therapeutic potential of the insect metalloproteinase inhibitor (IMPI) from Galleria mellonella, the only known specific inhibitor of M4 metalloproteinases. Methods The fusion protein IMPI‐GST (glutathione‐S‐transferase) was produced by fermentation in Escherichia coli and was tested for its ability to inhibit the proteolytic activity of the M4 metalloproteinases thermolysin and Pseudomonas elastase (PE), the latter a key virulence factor of the wound‐associated and antibiotic‐resistant pathogen Pseudomonas aeruginosa. We also tested the ability of IMPI to inhibit the secretome (Sec) of a P. aeruginosa strain obtained from a wound. Key findings We found that IMPI‐GST inhibited thermolysin and PE in vitro and increased the viability of human keratinocytes exposed to Sec by inhibiting detachment caused by changes in cytoskeletal morphology. IMPI‐GST also improved the cell migration rate in an in vitro wound assay and reduced the severity of necrosis caused by Sec in an ex vivo porcine wound model. Conclusions The inhibition of virulence factors is a novel therapeutic approach against antibiotic resistant bacteria. Our results indicate that IMPI is a promising drug candidate for the treatment of P. aeruginosa infections.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The therapeutic potential of the insect metalloproteinase inhibitor against infections caused by Pseudomonas aeruginosa

Eisenhardt

Schlupp

Höfer

et al. 2018

Journal of Pharmacy and Pharmacology

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“…A prime example is the development of AMPs from medicinal maggots of L. sericata which are formulated in hydrogels to test the efficacy of synthetic counterparts in wound dressings and as cosmetic ingredients to deter dermatological pathogens [ 21 , 104 , 119 ]. Other insect-derived AMPs such as the IMPI from G. mellonella [ 120 ] are currently also being developed for the therapy of chronic wounds [ 121 ]. Further promising medicinal applications of insect-derived AMPs are currently being explored in therapies to cure eye, lung and urogenital infections [ 117 , 122 , 123 ].…”

Section: Activity Screening and Medical Applications Of Insect Antimimentioning

confidence: 99%

Diversity, evolution and medical applications of insect antimicrobial peptides

Mylonakis

Podsiadłowski

Muhammed

et al. 2016

Phil. Trans. R. Soc. B

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197

192

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Antimicrobial peptides (AMPs) are short proteins with antimicrobial activity. A large portion of known AMPs originate from insects, and the number and diversity of these molecules in different species varies considerably. Insect AMPs represent a potential source of alternative antibiotics to address the limitation of current antibiotics, which has been caused by the emergence and spread of multidrug-resistant pathogens. To get more insight into AMPs, we investigated the diversity and evolution of insect AMPs by mapping their phylogenetic distribution, allowing us to predict the evolutionary origins of selected AMP families and to identify evolutionarily conserved and taxon-specific families. Furthermore, we highlight the use of the nematode Caenorhabditis elegans as a whole-animal model in high-throughput screening methods to identify AMPs with efficacy against human pathogens, including Acinetobacter baumanii and methicillin-resistant Staphylococcus aureus. We also discuss the potential medical applications of AMPs, including their use as alternatives for conventional antibiotics in ectopic therapies, their combined use with antibiotics to restore the susceptibility of multidrug-resistant pathogens, and their use as templates for the rational design of peptidomimetic drugs that overcome the disadvantages of therapeutic peptides.The article is part of the themed issue ‘Evolutionary ecology of arthropod antimicrobial peptides’.

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“…Peptides are good candidates for controlling wound infections. A drug carrier system was designed for delivering an insect metalloproteinase inhibitor (IMPI) drug to enable treatment of chronic wound infections [58]. Poly(lactic-co-glycolic acid) (PLGA) supplies lactate that accelerates neovascularization and promotes wound healing.…”

Section: Delivery Of Peptidesmentioning

confidence: 99%

Delivery Systems in Wound Healing and Nanomedicine

Fu¹

2016

Wound Healing - New Insights Into Ancient Challenges

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Introduction: Delivery systems in nanomedicine contribute to the improvements in wound healing, tissue regeneration, and anticancer pharmacological fields. Although various wound dressings have been used in wound care treatments, there is a great challenge in the wound management of ulcers, trauma, chronic wounds, and severe injury and burns, especially infected wounds. Body: To accelerate wound healing, influence tissue repair, reduce scarring, and control infection, various delivery devices have been developed in wound healing. The application of delivery devices has improved early as well as long-term wound care in delayed healing wounds. Main delivery systems are described, including drugs, bioactive proteins/growth factors, genes, and cells, outlining the advantages and limitations of each carrier in wound healing, as well as the mechanisms and release. This chapter reviews biomaterials and scaffolds that provide the carriers of bioactive agents, which include antimicrobial agents, combinations of cells, growth factors and genes, both scaffolds and cell interactions toward regeneration of skin tissues, vascular reconstructions, as well as transdermal carriers. In addition, the regulations, procedures, and clinical trails for delivery systems for wound healing are discussed. Conclusion: In the past decades, many wound dressings and skin substitutes have been developed to treat skin loss and wounds. Delivery systems can improve wound healing and tissue regeneration. Looking toward the future, the need for delivery wound healing products for chronic and complex wounds will increase. Functionalized delivery systems will probably be the academic interest and industrial focus on wound healing.

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Development of an insect metalloproteinase inhibitor drug carrier system for application in chronic wound infections

Abstract: This study reports the development of a poloxamer hydrogel as a suitable carrier system for the application of IMPI.

Cited by 9 publications

References 53 publications

The therapeutic potential of the insect metalloproteinase inhibitor against infections caused by Pseudomonas aeruginosa

The therapeutic potential of the insect metalloproteinase inhibitor against infections caused by Pseudomonas aeruginosa

Diversity, evolution and medical applications of insect antimicrobial peptides

Delivery Systems in Wound Healing and Nanomedicine

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