Inhibition of Pseudomonas aeruginosa Virulence: Characterization of the AprA-AprI Interface and Species Selectivity.
Summary of "Inhibition of Pseudomonas aeruginosa Virulence: Characterization of the AprA-AprI Interface and Species Selectivity."
Pseudomonas aeruginosa secretes the virulence factor alkaline protease (AprA) to enhance its survival. AprA cleaves one of the key microbial recognition molecules, monomeric flagellin, and thereby diminishes Toll-like receptor 5 activation. In addition, AprA degrades host proteins such as complement proteins and cytokines. P. aeruginosa encodes a highly potent inhibitor of alkaline protease (AprI) that is solely located in the periplasm where it is presumed to protect periplasmic proteins against secreted AprA. We set out to study the enzyme-inhibitor interactions in more detail in order to provide a basis for future drug development. Structural and mutational studies reveal that the conserved N-terminal residues of AprI occupy the protease active site and are essential for inhibitory activity. We constructed peptides mimicking the N-terminus of AprI; however, these were incapable of inhibiting AprA-mediated flagellin cleavage. Furthermore, we expressed and purified AprI of P. aeruginosa and the homologous (37% sequence identity) AprI of Pseudomonas syringae, which remarkably show species specificity for their cognate protease. Exchange of the first five N-terminal residues between AprI of P. syringae and P. aeruginosa did not affect the observed specificity, whereas exchange of only six residues located at the AprI surface that contacts the protease did abolish specificity. These findings are elementary steps toward the design of molecules derived from the natural inhibitor of the virulence factor AprA and their use in therapeutic applications in Pseudomonas and other Gram-negative infections.
Affiliation
Journal Details
This article was published in the following journal.
Name: Journal of molecular biology
ISSN: 1089-8638
Pages: 573-83
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22154939
- DOI: http://dx.doi.org/10.1016/j.jmb.2011.11.039
Medical and Biotech [MESH] Definitions
Pseudomonas Aeruginosa
A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. aeruginosa is a major agent of nosocomial infection.
Pyocyanine
Antibiotic pigment produced by Pseudomonas aeruginosa.
Pyocins
Bacteriocins elaborated by mutant strains of Pseudomonas aeruginosa. They are protein or protein-lipopolysaccharide complexes lethal to other strains of the same or related species.
Pseudomonas Phages
Viruses whose host is Pseudomonas. A frequently encountered Pseudomonas phage is BACTERIOPHAGE PHI 6.
Electrowetting
Reducing the SURFACE TENSION at a liquid/solid interface by the application of an electric current across the interface thereby enhancing the WETTABILITY of the surface.
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