Effects of sub-inhibitory concentrations of cell wall active antibiotics on virulence gene expression in Staphylococcus aureus

Infections caused by Staphylococcus aureus are a major concern to public health due to multifactorial virulence of the bacteria and increasing resistance to antimicrobial therapy. The bacterial cell wall continues to be the primary target for antibiotics used to treat staphylococcal infections. I have used promoter-lux reporter constructs to study the effects of sub-inhibitory concentrations of cell wall active antibiotics on virulence gene expression in S. aureus. Constructs made for virulence genes encoding Spa, an adhesin, RNAIII, a regulatory RNA molecule, and LukE, a leukotoxin E, were introduced into several strains of S. aureus. It was found that the effects of sub-inhibitory concentrations of antibiotics differed depending on the strain, and antibiotics affected the expression of virulence genes differently in the same strain. Based on the results with S. aureus strains lacking virulence regulators, SarA and SarS, it was concluded that sub-inhibitory concentrations of antibiotics modulate the expression of virulence regulators, which affects transcription of the downstream genes, spa and lukE. A speculative model for the mechanism of transcription modulation by antibiotics was proposed. The effect of sub-inhibitory concentrations of antibiotics on S. aureus biofilm formation was also studied. Finally, promoter-lux reporter constructs were used to investigate effects of various antibiotic combinations on gene expression in S. aureus.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat