Abstract
BackgroundDiscerning genes crucial to antimicrobial resistance (AMR) mechanisms is becoming more and more important to accurately and swiftly identify AMR pathogenic strains. Pangenome-wide association studies (e.g. Scoary) identified numerous putative AMR genes. However, only a tiny proportion of the putative resistance genes are annotated by AMR databases or Gene Ontology. In addition, many putative resistance genes are of unknown function (termed hypothetical proteins). An annotation tool is crucially needed in order to reveal the functional organization of the resistome and expand our knowledge of the AMR gene repertoire.ResultsWe developed an approach (PangenomeNet) for building co-functional networks from pan-genomes to infer functions for hypothetical genes. Using Escherichia coli as an example, we demonstrated that it is possible to build co-functional network from its pan-genome using co-inheritance, domain-sharing, and protein–protein-interaction information. The investigation of the network revealed that it fits the characteristics of biological networks and can be used for functional inferences. The subgraph consisting of putative meropenem resistance genes consists of clusters of stress response genes and resistance gene acquisition pathways. Resistome subgraphs also demonstrate drug-specific AMR genes such as beta-lactamase, as well as functional roles shared among multiple classes of drugs, mostly in the stress-related pathways.ConclusionsBy demonstrating the idea of pan-genome-based co-functional network on the E. coli species, we showed that the network can infer functional roles of the genes, including those without functional annotations, and provides holistic views on the putative antimicrobial resistomes. We hope that the pan-genome network idea can help formulate hypothesis for targeted experimental works.
Highlights
Antibiotic resistance is an emerging worldwide problem
To generate new strategies against resistance, we must know more about resistance mechanisms—how do those mobile elements and mutations change the dynamics of microbes? Are there new resistance genes within the pathogens that mandate therapeutic targeting? How quickly and how often do pathogens acquire antimicrobial resistance (AMR) genes? It has been hypothesized that antibiotic resistance trades off against fitness in the absence of antibiotics [3, 4], in which adaptive genes amplify against antimicrobial agents and are accompanied by compensatory mutations to tackle the fitness losses [5]
By building the pan-genome for the common pathogen Escherichia coli and using the pan-genome to build a co-functional network, we show that we are able to predict the functions for putative hypothetical genes and demonstrate their functional links with antibiotic resistances
Summary
Due to the misuse of antibiotics, emergence of highly resistant pathogens has again transformed the once conquered infectious diseases lethal To control those resistant pathogens, new drugs are needed. It has been hypothesized that antibiotic resistance trades off against fitness in the absence of antibiotics [3, 4], in which adaptive genes amplify against antimicrobial agents and are accompanied by compensatory mutations to tackle the fitness losses [5]. This indicates that the acquisition of resistance genes exposes new vulnerability in pathogens that may allow new strategies against resistance strains. An annotation tool is crucially needed in order to reveal the functional organization of the resistome and expand our knowledge of the AMR gene repertoire
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