A Systems-Level Approach for Investigating Pseudomonas aeruginosa Biofilm Formation

Abstract

Prevention of the initiation of biofilm formation is the most important step for combating biofilm-associated pathogens, as the ability of pathogens to resist antibiotics is enhanced 10 to 1000 times once biofilms are formed. Genes essential to bacterial growth in the planktonic state are potential targets to treat biofilm-associated pathogens. However, the biofilm formation capability of strains with mutations in these essential genes must be evaluated, since the pathogen might form a biofilm before it is eliminated. In order to address this issue, this work proposes a systems-level approach to quantifying the biofilm formation capability of mutants to determine target genes that are essential for bacterial metabolism in the planktonic state but do not induce biofilm formation in their mutants. The changes of fluxes through the reactions associated with the genes positively related to biofilm formation are used as soft sensors in the flux balance analysis to quantify the trend of biofilm formation upon the mutation of an essential gene. The essential genes whose mutants are predicted not to induce biofilm formation are regarded as gene targets. The proposed approach was applied to identify target genes to treat Pseudomonas aeruginosa infections. It is interesting to find that most essential gene mutants exhibit high potential to induce the biofilm formation while most non-essential gene mutants do not. Critically, we identified four essential genes, lysC, cysH, adk, and galU, that constitute gene targets to treat P. aeruginosa. They have been suggested by existing experimental data as potential drug targets for their crucial role in the survival or virulence of P. aeruginosa. It is also interesting to find that P. aeruginosa tends to survive the essential-gene mutation treatment by mainly enhancing fluxes through 8 metabolic reactions that regulate acetate metabolism, arginine metabolism, and glutamate metabolism.

Critical roles of arginine in growth and biofilm development by Streptococcus gordonii

“…For example, at physiological concentrations found in cystic fibrosis sputum, arginine promotes P. aeruginosa biofilm formation and prevents swarming motility (Bernier et al, 2011a). In model P. aeruginosa biofilms, arginine catabolism genes are upregulated compared with planktonic cells, leading to anaerobic metabolism and increased susceptibility to ciprofloxacin and tobramycin (Sauer et al, 2002;Borriello et al, 2004;Xu et al, 2013). Similarly, arginine deiminase activity is upregulated in S. aureus and S. pneumoniae biofilms compared with planktonic cells (Zhu et al, 2007;Allan et al, 2014).…”

A Novel Alkaloid from Marine-Derived Actinomycete Streptomyces xinghaiensis with Broad-Spectrum Antibacterial and Cytotoxic Activities

“…In addition to methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa strains which have caused serious healthcare-associated and community-onset infections [1], [2], Acinetobacter baumannii has received increasing attention recently as a persistent hospital pathogens due to the rapidly increasing number of infections among compromised and injured patients and the global spread of strains with resistance to multiple antibiotics [3], [4]. However, studies on novel antibiotics to treat drug resistant A. baumannii are still very limited [5].…”

A Genome‐Scale Modeling Approach to Quantify Biofilm Component Growth of Salmonella Typhimurium

“…The trend for biofilm formation, however, was not predicted in this paper. In order to address this issue, our group developed a systems‐biology approach to indicate the trend of biofilm formation of P. aeruginosa when single genes were inhibited (Xu and others ) and under various environmental conditions (Xu and others ). In particular, the change of intracellular fluxes in the genome‐scale model was used to indicate the trend of biofilm formation.…”