Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide.

Abstract

Pseudomonas aeruginosa elastase is a zinc metalloproteinase which is released during P. aeruginosa infections. Pseudomonas keratitis, which occurs following contact lens-induced corneal trauma, can lead to rapid, liquefactive necrosis of the cornea. This destruction has been attributed to the release of both host-derived enzymes and the bacterial products P. aeruginosa elastase, alkaline protease, exotoxin A, and lipopolysaccharide endotoxin. A synthetic metalloproteinase inhibitor, HSCH2 (DL)CH[CH2CH(CH3)2]CO-Phe-Ala-NH2, which we previously showed to be a potent inhibitor of corneal collagenase and alkali-induced corneal ulceration, was tested as a potential inhibitor of P. aeruginosa elastase. Inhibition constants (Kis) for the resolved diastereomers were determined with the chromogenic substrate furylacryloyl-glycyl-L-leucyl-L-alanine. One isomer had a Ki of 0.3 microM, while the other had a Ki of 0.4 microM. The more potent diastereomer was evaluated in vivo in experimentally induced Pseudomonas keratitis in rabbits. Following inoculation of one cornea of each rabbit, topical treatment with a 1 mM solution of the inhibitor significantly delayed the onset of corneal melting and perforation, as compared with the results for the control and gentamicin-treated groups. This protective effect suggests that the inhibitor may have a therapeutic application by delaying the progression of corneal destruction in Pseudomonas keratitis.

• Authors: F R Burns, C A Paterson, R D Gray, J T Wells
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 34 Issue 11 Pg. 2065-9 (Nov 1990) ISSN: 0066-4804 [Print] United States
• PMID: 2127341 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chromogenic Compounds
• Dipeptides
• Gentamicins
• Sulfhydryl Compounds
• mercaptomethyl-4-methylpentanoyl-phenylalanylalaninamide
• Pancreatic Elastase
• Metalloendopeptidases

Topics

• Amino Acid Sequence
• Animals
• Chromogenic Compounds (metabolism)
• Cornea (microbiology)
• Dipeptides (pharmacology)
• Eye Infections, Bacterial (drug therapy, microbiology)
• Gentamicins (therapeutic use)
• Keratitis (drug therapy, microbiology)
• Metalloendopeptidases (antagonists & inhibitors)
• Molecular Sequence Data
• Pancreatic Elastase (antagonists & inhibitors, isolation & purification)
• Pseudomonas Infections (drug therapy, microbiology)
• Pseudomonas aeruginosa (enzymology)
• Rabbits
• Sulfhydryl Compounds (pharmacology)