The therapeutic potential of the insect metalloproteinase inhibitor against infections caused by Pseudomonas aeruginosa. (8th November 2018)

• Record Type: Journal Article
• Authors: Eisenhardt, Michaela; Schlupp, Peggy; Höfer, Frank; Schmidts, Thomas; Hoffmann, Daniel; Czermak, Peter; Pöppel, Anne-Kathrin; Vilcinskas, Andreas; Runkel, Frank
• Is Part Of: Journal of pharmacy and pharmacology. Volume 71:Number 3(2019)
• Page Start: 316
• Page End: 328
• Publication Date: 2018-11-08
• Subjects: IMPI -- Pseudomonas aeruginosa secretome -- Pseudolysin -- LasB -- ex vivo porcine wound model; Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.13034
• Languages: English
• ISSNs: 0022-3573

Abstract

Abstract: 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.