A Systems Level Approach for Identification of Molecular Targets for Antimicrobial Intervention against Pseudomonas Aeruginosa, while Predicting Biofilm Formation

In this case study, we aimed at evaluating the suitability of genome-scale metabolic models to identify molecular targets that can potentially enhance antimicrobial effects of chemical preservatives against P. aeruginosa, while minimizing biofilm formation. For the case study, isothiazolinones were selected as a group of microbicides where their mechanism of action is well described in scientific literature. Target identification was carried out in several steps. First, we developed a computational model of P. aeruginosa metabolism under action of isothiazolinones. Action of sub-inhibitory concentrations of isothiazolinones was simulated based on extensive information on their mechanisms of action. Then, simulations of single and double gene deletion(s) were performed in silico to identify genes or combinations of genes that could be targeted to induce further reduction of bacterial growth rate. Finally, we assessed whether total or partial inhibition of these genes might activate biofilm formation.