Comparative Tn-Seq reveals common daptomycin resistance determinants in Staphylococcus aureus despite strain-dependent differences in essentiality of shared cell envelope genes
2019
Antibiotic-resistant Staphylococcus aureus remains a leading cause of antibiotic resistance-associated mortality in the United States. Given the reality of multi-drug resistant infections, it is imperative that we establish and maintain a pipeline of new compounds to replace or supplement our current antibiotics. A first step towards this goal is to prioritize targets by identifying the genes most consistently required for survival across the S. aureus phylogeny. Here we report the first direct comparison of gene essentiality across multiple strains of S. aureus via
transposon sequencing. We show that mutant fitness varies by strain in key pathways, underscoring the importance of using more than one strain to differentiate between core and strain-dependent
essential genes. Despite baseline differences in gene importance, several pathways, including the
lipoteichoic acidpathway, become consistently essential under
daptomycinexposure, suggesting core vulnerabilities that can be exploited to resensitize
daptomycin-nonsusceptible isolates. We also demonstrate the merit of using transposons with outward-facing promoters capable of overexpressing nearby genes for identifying clinically-relevant gain-of-function resistance mechanisms. Together, the
daptomycinvulnerabilities and resistance mechanisms support a mode of action with wide-ranging effects on the
cell envelopeand cell
division. This
workadds to a growing body of literature demonstrating the nuanced insights gained by comparing Tn-Seq results across multiple bacterial strains.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
85
References
5
Citations
NaN
KQI