Genes Contributing to Staphylococcus aureus Fitness in Abscess- and Infection-Related Ecologies

Abstract

Staphylococcus aureus is a leading cause of both community- and hospital-acquired infections that are increasingly antibiotic resistant. The emergence of S. aureus resistance to even last-line antibiotics heightens the need for the development of new drugs with novel targets. We generated a highly saturated transposon insertion mutant library in the genome of S. aureus and used Tn-seq analysis to probe the entire genome, with unprecedented resolution and sensitivity, for genes of importance in infection. We further identified genes contributing to fitness in various infected compartments (blood and ocular fluids) and compared them to genes required for growth in rich medium. This resulted in the identification of 426 genes that were important for S. aureus fitness during growth in infection models, including 71 genes that could be considered essential for survival specifically during infection. These findings highlight novel as well as previously known genes encoding virulence traits and metabolic pathways important for S. aureus proliferation at sites of infection, which may represent new therapeutic targets.

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

“…A number of recent S. aureus transposon-sequencing (TnSeq) studies have been carried out to identify genes that potentially contribute to fitness in vivo and/or during infection (33,34). We hypothesized that if a PPIase contributes to the folding/activity of Nuc, it is likely that the corresponding mutant would have decreased virulence/fitness in vivo.…”

“…Interestingly, mutants in each of the three PPIase genes demonstrated fitness defects under different conditions. A ppiB mutant had decreased fitness in an abscess model of infection (34), while a prsA mutant had decreased fitness in human blood and during osteomyelitis infection (33,34). A tig mutant demonstrated decreased fitness in abscess and osteomyelitis infection models (33,34).…”

Genome-wide screen for genes involved in eDNA release during biofilm formation by Staphylococcus aureus

“…optimize conditions, which used a lower density transposon insertion library (13), eight of the genes listed in Table 1 (alsT, fmtA, ptsI, SAOUHSC_00034, recF, tcyA, ansA, and lpl2A) were also identified by using the same cutoff criteria. Several genes identified in this eDNA release screen are involved in nucleotide metabolism.…”

Raf-Kinase Inhibitor Gw5074 Shows Antibacterial Activity Against Methicillin-Resistant Staphylococcus Aureus and Potentiates the Activity of Gentamicin

“…A highly saturated mariner insertion library constructed in S. aureus HG003 [23] was obtained as a gift from M Gilmore (MGH, Massachusetts Eye and Ear Infirmary). A frozen aliquot of the library was diluted 1:1000 in 40 ml BHI medium and incubated at 37°C overnight with shaking at 200 rpm.…”

“…In further efforts to uncover the mechanism of antimicrobial action of GW5074, we screened the highly saturated mariner library [23] of S. aureus strain HG003 Enterococcus faecium E007 8…”