Abstract
Virulence-linked pathways in opportunistic pathogens are putative therapeutic targets that may be associated with less potential for resistance than targets in growth-essential pathways. However, efficacy of virulence-linked targets may be affected by the contribution of virulence-related genes to metabolism. We evaluate the complex interrelationships between growth and virulence-linked pathways using a genome-scale metabolic network reconstruction of Pseudomonas aeruginosa strain PA14 and an updated, expanded reconstruction of P. aeruginosa strain PAO1. The PA14 reconstruction accounts for the activity of 112 virulence-linked genes and virulence factor synthesis pathways that produce 17 unique compounds. We integrate eight published genome-scale mutant screens to validate gene essentiality predictions in rich media, contextualize intra-screen discrepancies and evaluate virulence-linked gene distribution across essentiality datasets. Computational screening further elucidates interconnectivity between inhibition of virulence factor synthesis and growth. Successful validation of selected gene perturbations using PA14 transposon mutants demonstrates the utility of model-driven screening of therapeutic targets.
Highlights
Virulence-linked pathways in opportunistic pathogens are putative therapeutic targets that may be associated with less potential for resistance than targets in growth-essential pathways
We present an updated genome-scale metabolic network models (GEMs) of P. aeruginosa strain PAO1 as well as a new GEM of P. aeruginosa strain PA14
We assigned potential roles to 59 and 44 genes annotated as hypothetical proteins in PAO1 and PA14 genome annotations from the Pseudomonas Genome Database (PGD), respectively
Summary
Virulence-linked pathways in opportunistic pathogens are putative therapeutic targets that may be associated with less potential for resistance than targets in growth-essential pathways. Traditional antibiotics that inhibit growth of bacteria by targeting growth-essential functions actively select for antibiotic-resistant mutants that overtake the infection. Inhibiting mechanisms of infection by targeting the synthesis of virulence factors (VFs) and virulence-linked genes may be a promising new therapeutic strategy that avoids growth-based target selection, improves patient outcomes and mitigates the spread of resistance[1,3,4]. Virulence-linked genes contribute to survival and fitness within a host Many of these genes encode the synthesis pathways of VFs, pathogen-produced small molecules that are involved in activities such as iron sequestration and bacterial communication that enable adaptation to the host environment and enhance infection potential[5,6]. Assembled from annotated genomic data, GEMs are mathematical frameworks that incorporate biochemical, genetic and cell phenotypic data and account for hundreds to thousands of gene-protein-reaction (GPR) relationships and reaction stoichiometry and directionality[9]; they have been used to predict novel drug targets that inhibit growth[10] as well as probe the capability of an organism to synthesize various metabolites[11], including VFs (ref. 12)
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