INTERACTION BETWEEN THE PILI OF PSEUDOMONAS-AERUGINOSA PAK AND ITS CARBOHYDRATE RECEPTOR BETA-D-GA1NAC(1-]4)BETA-D-GAL ANALOGS

Pseudomonas aeruginosa employs pill to mediate adherence to epithelial cell surface receptors. Previously, it has been shown that the pilus adhesin of P. aeruginosa PAK binds to the ganglioside asialo-GM(1). In particular, it was found that the carbohydrate sequence beta-D-GalNAc (1-->4)beta-D-Gal is the minimal carbohydrate receptor sequence of asi alo-GM(1). To study the binding specificity of P. aeruginosa, O-modifi ed and N-modified sugar analogs, where each hydroxyl group was substit uted either by O-methyl or O-propyl and the acetamido group was change d to a propionamido group, were synthesized. The sugar analogs were ev aluated as inhibitors in a competitive solid phase binding assay. The results demonstrate that the pill of P. aeruginosa PAK accepts a varie ty of sugar analogs possessing the sequence beta-D-GalNAc(1-->4)beta-D -Gal. Most sugar analogs bind with a similar order of magnitude (50% i nhibitory concentration (IC50) = 60-130 mu M) except for the 2-O-propy l derivative 7 (IC50 = 8 +/- 4 mu M) compared with an IC50 of 79 +/- 1 8 mu M for the native compound. The significant increase in binding af finity of 2-O-propyl derivative 7 suggests that improved inhibitors of adhesion may be prepared by introducing a hydrophobic side chain at t he 2-position of galactose.