Colistin stimulates the activity of neutrophil elastase and Pseudomonas aeruginosa elastase.
Nonantimicrobial effects of antibiotics may contribute to their activity in the treatment of infective airway disease. The aim of this study was to identify antibiotics used for the treatment of infection in cystic fibrosis that may alter the activity of human neutrophil elastase (HNE) and Pseudomonas aeruginosa elastase (PE). The effect of antibiotics on the activity of purified HNE and PE, and HNE in sputum was assessed using colourimetric and fluorescent substrate assays by kinetic measurements, and by examining the interaction of HNE with inhibitors. Ceftazidime, tobramycin, and gentamycin slightly inhibited purified HNE activity whereas erythromycin and colistin significantly stimulated purified HNE and PE (395 and 557%, respectively). However, only colistin increased HNE activity in sputum (+102%) and was therefore studied in more detail. This increase in activity was not due an interference with the specific inhibition of HNE by alpha1-antitrypsin but colistin was found to reverse the inhibitory effects of small molecular weight molecules like heparin. Colistin increases the activity of human neutrophil elastase and Pseudomonas aeruginosa elastase, two proteases that contribute to the pathogenesis of cystic fibrosis airway disease.
Jones
A
A
Child Health-Division of Clinical Sciences, Sheffield Children's Hospital Trust, UK.
Elphick
H
H
Pettitt
E
E
Everard
M L
ML
Evans
G S
GS
D000293:Adolescent; D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism*; D002442:Ceftazidime / Q000494:pharmacology; D002648:Child; D003091:Colistin / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000382:microbiology; D004789:Enzyme Activation / Q000187:drug effects; D004917:Erythromycin / Q000494:pharmacology; D005260:Female; D005839:Gentamicins / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000201:enzymology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013183:Sputum / Q000187:drug effects / Q000201:enzymology; D014031:Tobramycin / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D001426:Bacterial Proteins; D005839:Gentamicins; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D004917:Erythromycin; C026704:methoxysuccinyl-alanyl-alanyl-prolyl-valine chloromethyl ketone; D006493:Heparin; D002442:Ceftazidime; D019272:Leukocyte Elastase; D008666:Metalloendopeptidases; C043859:pseudolysin, Pseudomonas aeruginosa; D014031:Tobramycin; D003091:Colistin