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.
This article was published in the following journal.
Name: Journal of molecular biology
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22154939
- DOI: http://dx.doi.org/10.1016/j.jmb.2011.11.039
Infections of Pseudomonas aeruginosa are of great concern because of its increasing resistance towards conventional antibiotics. Quorum sensing system of P. aeruginosa acts as a global regulator of al...
Pseudomonas aeruginosa produces multiple virulence factors that have been associated with quorum sensing. The aim of this study was to evaluate the prevalence of drug resistant profiles and quorum sen...
Pseudomonas aeruginosa is an important etiological agent associated with systemic infection in burn patients. Quorum sensing (QS) mechanism of P. aeruginosa contributes to its virulence. Inhibition of...
Previous work showed that PA5542 inactivation increases Pseudomonas aeruginosa 59.20 susceptibility to carbapenems. The objective of the current study was to purify PA5542, to determine its role in ca...
The respiratory tract of cystic fibrosis (CF) patients harbor persistent microbial communities (CF airway microbiome) with Pseudomonas aeruginosa emerging as a dominant pathogen. Within a polymicrobia...
This is an open-label, single arm (uncontrolled) study in subjects suffering from cystic fibrosis, who have completed their study participation in CTBM100C2303 (all visits) and who were pr...
The objectives of this open study are to assess the safety, tolerability, pharmacokinetics and clinical outcome of patients who have HAP caused by Pseudomonas aeruginosa serotype O11 after...
OBJECTIVES: I. Assess the efficacy of monthly intravenous mucoid exopolysaccharide Pseudomonas aeruginosa immune globulin (MEP IGIV) given over 1 year in reducing the frequency of acute p...
The purpose of this study is to determine whether the nasal inhalation of Colistin is effective to decrease the Pseudomonas aeruginosa bacterial count in the nasal lavage fluid.
The purpose of this study is to assess the clinical efficacy of azithromycin, used as a quorum-sensing blocker, when compared to placebo for preventing or delaying the occurrence of pneum...
Medical and Biotech [MESH] Definitions
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.
Antibiotic pigment produced by Pseudomonas aeruginosa.
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.
Viruses whose host is Pseudomonas. A frequently encountered Pseudomonas phage is BACTERIOPHAGE PHI 6.
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.