Pseudomonas aeruginosa alginate in cystic fibrosis sputum and the inflammatory response. target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed second-generation antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB, = 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in biofilm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal biofilms, and to eradicate biofilm completely when used in combination with conventional antibiotics. INTRODUCTION Bacterial toxins, with enzymatic activity on mammalian tissues, include some of the most Rabbit polyclonal to AHRR toxic substances known. Tetanus toxin, botulinum toxin, and anthrax toxin are key examples, each of which is definitely a zinc-metalloprotease virulence element secreted by its respective bacterial strain (8). Pseudolysin is the important zinc metalloprotease virulence element secreted from the opportunistic pathogen and is also known as LasB or pseudomonas Dexamethasone elastase (32). This virulence element is definitely highly harmful, causing tissue damage and invasion, processing components of the immune system to cause immunomodulation (58), and acting intracellularly to initiate bacterial biofilm growth (20). These three collective virulence mechanisms of LasB are potentially of great significance in the progression to a chronic illness. First, the direct tissue damage in the sponsor liberates nutrients for bacterial growth, accelerating the general assault on sponsor cells. This also contributes to an excess of proteolytic activity at the site of illness that upsets the balance of proteolysis in the sponsor. Second, the action of LasB on components of the immune system and the immunomodulation that results manipulate Dexamethasone Dexamethasone the sponsor immune system into a harmful inflammatory cycle (28). Third, LasB initiates the biofilm pathway through activation of nucleoside diphosphate kinase (NDK) within the bacterial cell (20). Once created, biofilms are highly resistant to the immune response and to antibiotics. The inflammatory response raised against the biofilm matrix is definitely ineffectual in clearing the biofilm and instead perpetuates the inflammatory cycle in the sponsor (17, 29, 34, 43). The biofilm also releases planktonic bacterial cells, again contributing to the inflammatory response and keeping the infection (18). Chronic pseudomonal infections are therefore characterized by a protracted self-perpetuating vicious cycle of host-derived swelling and tissue damage that is well defined and that impedes the normal clearance of the bacteria (47). The balance is Dexamethasone definitely tipped toward an environment with excess immune, inflammatory, oxidative, and proteolytic activity, which in turn causes further swelling and damage. The influence of LasB is definitely a potential underlying trigger of this sustained host-derived inflammatory environment that persists during chronic intractable infections by recognized as the key pathogen. Exacerbations of CF are chronic biofilm-based infections and are characterized by a sustained alteration in the balance of host swelling (44). However, several other chronic pseudomonal infections are also characterized by misdirected and chronic inflammatory and immune responses that display homology to the vicious cycle in the CF lung. These include leg ulcers, burn infections, septicemia, keratitis, and pneumonia (2, 15, 16, 45, 48, 49, 62). The collective virulence mechanisms of LasB, consequently, implicate the protease as a key target for virulence inhibition. The attenuation of LasB-mediated virulence could simultaneously inhibit the harmful action of LasB in the sponsor and exert an antibiofilm effect in the bacterial cell. It is hoped that this antivirulence mechanism might prevent the delicate mechanisms by which LasB is definitely proposed to evade and manipulate the host immune.
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