Intervention in bacterial adhesion to host cells is a novel method of overcoming current problems associated with antibiotic resistance. Antibiotic-resistant strains of bacteria that cause respiratory tract infections are a problem in hospitals and could be used in bioterrorist attacks. A range of bacterial species was demonstrated to attach to an alveolar epithelial (A549) cell line. In all cases, cell surface oligosaccharides were important in attachment, demonstrated by reduced adhesion when A549 cells were pre-treated with tunicamycin. Bacillus anthracis and Yersinia pestis displayed a restricted tropism for oligosaccharides compared to the environmental, opportunistic pathogens, Pseudomonas aeruginosa, Burkholderia cenocepacia, Burkholderia pseudomallei and Legionella pneumophila. The compound with the greatest anti-adhesion activity was p-nitrophenol. Other generic attachment inhibitors included the polymeric saccharides (dextran and heparin), GalNAcâ1-4Gal, GalNAcâ1-3Gal, Galâ1-4GlcNAc and Galâ1-3GlcNAc. Burkholderia pseudomallei attachment was particularly susceptible to oligosaccharide inhibition. Combinations of such compounds may serve as a novel generic therapeutics for respiratory tract infections.
INTRODUCTIONThe development of antibiotic resistance amongst pathogenic bacteria is a frequent occurrence and of great concern for public health. This problem is associated with many bacteria that cause community-and hospital-acquired pneumonia such as Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa and Burkholderia cenocepacia (Lister, 2000;Lynch, 2001;Spencer, 1995;Tan, 2003). Problems with antibiotic resistance can also extend to those bacteria that could be used in bioterrorism. It is likely that such bacterial threat agents would be delivered by the aerosol route resulting in respiratory presentation of the disease (Cieslak & Eitzen, 2000;Leggiadro, 2000). Given the ease of natural acquisition of antibiotic resistance genes and genetic manipulation, it is prudent to research therapeutic alternatives to antibiotics.Attachment to cell surfaces is one of the key steps in bacterial pathogenesis, often involving oligosaccharides located on the host cell surface and bacterial adhesins (Karlsson et al., 1992;Ofek & Sharon, 1990). The terminal di-or trisaccharide units of these oligosaccharides may be used to inhibit these interactions, preventing attachment and hence disease (Zopf & Roth, 1996). The theory has been proven in vitro with a range of bacterial species. For example, lacto-N-neotetraose and asialoganglioside-GM1 (asialo-GM1) inhibit attachment of S. pneumoniae to alveolar epithelial cells (Tong et al., 1999). Similarly 3-sialyllactose inhibits Helicobacter pylori attachment to gastric epithelial cells . Asialoganglioside-GM1 and -GM2 are used as receptors by a number of respiratory pathogens, which specifically bind their terminal GalNAcâ1-3Gal and GalNAcâ1-4Gal moieties (Krivan et al., 1988a(Krivan et al., , b, 1991. The principle has also been proven to be valid in vivo...