Pseudomonas aeruginosa is a malicious opportunistic pathogen both in terms of the severity and the outcome of infections it causes. A significant proportion of patients with cystic fibrosis (CF) is colonized at an early age (1-2yrs), and most ultimately succumbs to a chronic lung infection from P. aeruginosa. The myriad of virulence determinants, including colonization factors and toxins that P. aeruginosa produces contribute to its pathogenic potential. Unfortunately, the exact contribution of these factors, alone or in combination, to even the simplest kind of P. aeruginosa infection has not yet been elucidated. Expression of all the identified major virulence determinants in this organism is regulated by a variety of environmental conditions, which the organism encounters at some point in its journey through the host. Consequently, variations in available environmental iron undoubtedly contribute to the pathogenesis of P. aeruginosa infections. Production of specific virulence factors of this organism are induced in response to limiting amounts of iron, a natural occurring environment in mammalian hosts. The dynamic control of intracellular iron concentrations is paramount to all biological systems. One aspect of this issue is that, especially in an aerobic environment, biologically useful iron (i.e., Fe 2+) is extremely limiting or it is highly insoluble (i.e.,Fe3+). Accordingly, biological entities have evolved efficient mechanisms to acquire this nutrient from the insoluble form, which is generally in plentiful quantities. On the other hand, further acquisition of iron above biologically useful concentrations can have dire consequences for a cell. Excess free iron will catalyze the generation of highly reactive oxygen and nitrogen intermediates that will damage all known biological macromolecules. This conflict, in a major way is dealt with in a diverse array of pathogenic and commensal prokaryotic microbes, by repressor proteins, which play the key role in controlling iron homeostasis at the level of transcription. The ferric uptake regulator (Fur) serves this function in many bacteria. In fact, in the opportunistic pathogen P. aeruginosa, Fur (PA-Fur) is an essential protein that controls the expression of genes involved in the acquisition of environmental iron, including those that contribute to its virulence. This project will investigate the role of PA-Fur and PA-Fur regulated genes in the pathogenesis of P. aeruginosa infections for the ultimate goal or developing novel antimicrobial agents against this formidable opportunist. ? ?
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