chondroitin-sulfates and Pseudomonas-Infections

Cystic fibrosis (CF) is associated with mutation and abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) that affects cellular chloride transport. Clinically, CF of the lung is associated with excessive accumulation of secretions, including the sulfated glycosaminoglycans, chondroitin sulfate and dermatan sulfate (DS), both of which contain sulfated N-acetylgalactosamine residues. The sulfatase enzymes, which are a highly conserved group of enzymes with high specificity for designated sulfate groups, include arylsulfatase B, a lysosomal enzyme. Arylsulfatase B, also known as N-acetyl galactosamine 4-sulfatase, can degrade DS and chondroitin-4 sulfate. Previously reported data demonstrated diminished activity of arylsulfatase B in lymphoid cell lines of patients with CF compared to normal control subjects. Frequent infections with Pseudomonas, a sulfatase-producing organism, occur in patients with CF, whereas infections with Mycobacterium tuberculosis, which lacks sulfatase activity, are infrequent. Additional investigation to determine if diminished function of arylsulfatase B is a consistent finding in cells of patients with CF may be informative, and may help to correlate the molecular, biochemical, and clinical characteristics of CF.

Topics: Bacterial Infections; Chondroitin Sulfates; Cystic Fibrosis; Dermatan Sulfate; Glycosaminoglycans; Humans; Ion Exchange; Lung; Mucopolysaccharidosis VI; N-Acetylgalactosamine-4-Sulfatase; Pseudomonas Infections; Sodium; Sulfates; Tuberculosis

Bacterial keratitis is an ocular infection with the potential to cause significant visual impairment. Increasing patterns of antibiotic resistance have necessitated the development of new antimicrobial agents for use in bacterial keratitis and other serious ocular infections. With a view to exploring the use of novel antimicrobial peptides in the management of ocular infection, we performed a series of experiments using synthetic antimicrobial peptides designed for the eradication of common and serious ophthalmic pathogens.. Experiments were performed with three clinical ocular isolates--Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis--in three experimental settings: (1) in vitro in a controlled system of 10 mM sodium phosphate buffer, (2) in vitro in modified chondroitin sulfate-based corneal preservation media (Optisol), and (3) in an in vivo animal model (rabbit) simulating bacterial keratitis. In all cases, outcomes were measured by quantitative microbiological techniques.. The candidate peptides (CCI A, B, and C and COL-1) produced a total reduction of the test pathogens in phosphate buffered saline. In modified Optisol, the peptides were effective against S epidermidis at all temperatures, demonstrated augmented activity at 23 degrees C against the gram-positive organisms, but were ineffective against P aeruginosa. The addition of EDTA to the medium augmented the killing of P aeruginosa but made no difference in the reduction of gram-positive organisms. In an in vivo rabbit model of Pseudomonas keratitis, COL-1 demonstrated neither clinical nor microbicidal efficacy and appeared to have a very narrow dosage range, outside of which it appeared to be toxic to the ocular surface.. Our data indicate that the antimicrobial peptides we tested were effective in vitro but not in vivo. In an age of increasing antibiotic resistance, antimicrobial peptides, developed over millions of years as innate defense mechanisms by plants and animals, may have significant potential for development as topical agents for the management of severe bacterial keratitis. However, modifications of the peptides, the drug delivery systems, or both, will be necessary for effective clinical application.

Topics: Animals; Anti-Bacterial Agents; Chondroitin Sulfates; Complex Mixtures; Cornea; Culture Media, Serum-Free; Dextrans; Eye Infections, Bacterial; Gentamicins; Humans; Keratitis; Organ Preservation; Peptide Fragments; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Sheep; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis