Treatments against Pseudomonas aeruginosa Biofilms in Cystic Fibrosis Patient Lungs

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Introduction

Cystic fibrosis Cystic Fibrosis (CF), is the most common autosomal recessive genetic disorder of Caucasians in America. Mutations in the CFTR gene cause the chloride channel to malfunction in CF patients, leading to impaired mucociliary clearance of inhaled microbes. Principal mechanisms of lung defense against bacterial colonization include mucociliary clearance, polymorphonuclear neutrophil phagocytosis and local production of antibacterial cationic peptides. However, these defense systems are ineffective against the conditions of increased osmolarity and viscosity in the lungs, and result in chronic lung infection, most frequently by Pseudomonas aeruginosa. The P. aeruginosa infections survive in the lungs of CF patients due to the adaptive mechanism of biofilm formation. Biofilms are surface attached microbial communities that are surrounded by an extracellular matrix and have great resistance to antibiotics. P. aeruginosa biofilms cause chronic infection because they resist phagocytosis, in addition to other components of the immune system, and have increased tolerance of antibiotic treatments. These bacterial populations are able to adapt to the highly compartmentalized and anatomically deteriorating lung environment of CF patients. Despite rigorous antibiotic and therapeutic therapies, chronic P. aeruginosa lung infections are rarely, if ever, eliminated permanently.

Bacteria in CF lungs & Biofilm Formation

The malfunctioning of CFTR gene causes the body of a CF patient to produce unusually thick and sticky mucus. This mucus builds up and clogs the lungs and pancreas; this obstruction makes breathing very difficult. Copious amounts of sputum are produced in the lungs, which impairs mechanical clearance mechanisms. Bacterial colonization is probably promoted by the unique composition of sputum within the CF lung environment (Microcolony formation: a novel biofilm model of Pseudomonas aeruginosa for the cystic fibrosis lung). CF makes patients susceptible to a broad spectrum of disease phenotypes including failure of lung function and even death. A limited range of microorganisms can colonize the CF lung, and P. aeruginosa in particular is most associated with a decline in lung deterioration and health. Chronic lung infections of P. aeruginosa are the major cause of morbidity and mortality in CF patients (M. J. Goldmanet al., Cell 88, 553 (1997). Once formed, these bacterial populations are unmanageable to treatment, mainly due to a biofilm mode of growth. This growth in CF patients’ lungs accompanies an increased frequency of mutations, as well as the adaption of P. aeruginosa to the inflammatory defense mechanism to the lungs and antibiotic treatments. Mechanisms of resistance such as upregulated efflux pumps, mutations of antibiotic target molecules in the bacteria and chromosomal β-lactamase aid P.aeruginosa survival. These conventional resistance mechanisms and formation of mucoid biofilms, biofilms with alginate as a large part of the polysaccharide protection, allow P. aeruginosa to survive for decades despite the antibiotic therapy, while the lung tissue is gradually destroyed. The immense antibiotic resistance may be attributed to low bacterial metabolic activity and increased doubling times of the bacterial cells in CF lungs. Although there are numerous variants of the P. aeruginosa isolated from CF patients, the most common variant found was the mucoid phenotype, a key step in the establishment of chronic lung infection, typically involving the acquisition of stable mutations.