Antibacterial activity of lysozyme and lactoferrin is inhibited by binding of advanced glycation-modified proteins to a conserved motif.

Abstract

Why diabetes is associated with abnormally high susceptibility to infection remains unknown, although two major antibacterial proteins, lysozyme and lactoferrin, have now been shown to specifically bind glucose-modified proteins bearing advanced glycation end products (AGEs). Exposure to AGE-modified proteins inhibits the enzymatic and bactericidal activity of lysozyme, and blocks the bacterial agglutination and bacterial killing activities of lactoferrin. Peptide mapping revealed a single AGE binding domain in lysozyme and two AGE binding domains in lactoferrin; each domain contains a 17- to 18- amino acid cysteine-bounded loop motif (CX15-16C) that is markedly hydrophilic. Synthetic peptides corresponding to these motifs in lysozyme and lactoferrin exhibited AGE binding activity, and similar domains are also present in other antimicrobial proteins. These results suggest that elevated levels of AGEs in tissues and serum of diabetic patients may inhibit endogenous antibacterial proteins by binding to this conserved AGE-binding cysteine-bounded domain 'ABCD' motif, thereby increasing susceptibility to bacterial infections in the diabetic population.