Abstract
Burkholderia cenocepacia is among the important pathogens isolated from cystic fibrosis (CF) patients. It has attracted considerable attention because of its capacity to evade host immune defenses during chronic infection. Advances in systems biology methodologies have led to the emergence of methods that integrate experimental transcriptomics data and genome-scale metabolic models (GEMs). Here, we integrated transcriptomics data of bacterial cells grown on exponential and biofilm conditions into a manually curated GEM of B. cenocepacia. We observed substantial differences in pathway response to different growth conditions and alternative pathway susceptibility to extracellular nutrient availability. For instance, we found that blockage of the reactions was vital through the lipid biosynthesis pathways in the exponential phase and the absence of microenvironmental lysine and tryptophan are essential for survival. During biofilm development, bacteria mostly had conserved lipid metabolism but altered pathway activities associated with several amino acids and pentose phosphate pathways. Furthermore, conversion of serine to pyruvate and 2,5-dioxopentanoate synthesis are also identified as potential targets for metabolic remodeling during biofilm development. Altogether, our integrative systems biology analysis revealed the interactions between the bacteria and its microenvironment and enabled the discovery of antimicrobial targets for biofilm-related diseases.
Highlights
Cystic fibrosis (CF) is the most common form of the autosomal recessive disease in Caucasians and affects 1 in every 3000–3500 births in Europe and United States [1]
Reactions involved in lipid metabolism constitute the majority (n = 103, 59.2%) of the single lethal reactions; among these lipid metabolism reactions, fatty acid biosynthesis (n = 62, 60.2%) was most frequently found
Altered metabolic fluxes were identified from the synthetic lethality analysis as well as condition-specific models based on gene expression profile
Summary
Cystic fibrosis (CF) is the most common form of the autosomal recessive disease in Caucasians and affects 1 in every 3000–3500 births in Europe and United States [1]. Many risk factors are implicated in the development and progression of CF lung disease, such as chronic infections by biofilm-forming pathogens. Complex metabolic responses in biofilms may have a fundamental role in the pathogenesis of this chronic disease [3]. Burkholderia cepacia complex (Bcc) emerged as important pathogens in the airways of immunocompromised humans, especially those with CF. The treatment of Bcc infections is challenging because of the natural resistance to various classes of antibiotics and long-term colonization, and the ability to adapt to nutrient-deficient biofilm microenvironment [4]. There is an urgent need to develop efficient drugs to improve and preserve lung function early on in patients’ life since chronic infection with Bcc is an independent predictor associated with poor prognosis [5]. The eradication of Bcc remains challenging, and there are large gaps in our current understanding of the underlying biochemical and molecular mechanisms involved in the persistence of biofilms
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