Published on Tue Aug 24 2021

Species-scale genomic analysis of S. aureus genes influencing phage host range and their relationships to virulence and antibiotic resistance genes

Moller, A. G., Petit, R. A., Read, T. D.

Phage therapy has been proposed as a possible alternative treatment for infections caused by the ubiquitous bacterial pathogen S. aureus. Successful phage therapy requires knowing both host and phage genetic factors influencing host range for rational cocktail formulation.

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Abstract

Phage therapy has been proposed as a possible alternative treatment for infections caused by the ubiquitous bacterial pathogen S. aureus. However, successful phage therapy requires knowing both host and phage genetic factors influencing host range for rational cocktail formulation. To further our understanding of host range, we searched 40,000+ public S. aureus genome sequences for previously identified phage resistance genes. We found that phage adsorption targets and genes that block phage assembly were significantly more conserved than genes targeting phage biosynthesis. Core phage resistance genes had similar nucleotide diversity, ratio of non-synonymous to synonymous substitutions, and functionality (measured by delta-bitscore) to other core genes in a set of 380 non-redundant S. aureus genomes (each from a different MLST sequence type). Non-core phage resistance genes were significantly less consistent with the core genome phylogeny than all non-core genes in this set. Only superinfection immunity genes correlated with empirically determined temperate phage resistance, accessory genome content, and numbers of accessory antibiotic resistance or virulence genes encoded per strain. Taken together, these results suggested that, while phage adsorption genes are heavily conserved in the S. aureus species, they are not undergoing positive selection, arms race dynamics. They also suggested genes classified as involved in assembly are least phylogenetically constrained and superinfection immunity genes best predict both empirical phage resistance and levels of phage-mediated HGT.