Abstract
Staphylococcus aureus is an important pathogen in hospital and community infections. Fusidic acid is particularly effective in treating skin and wound infections caused by staphylococci. The purpose of our study was to clarify the effect of fusidic acid on the biofilm formation and α-toxin expression of S. aureus at subinhibitory concentrations [1/64, 1/32, and 1/16 × minimum inhibitory concentration (MIC)]. A total of 504 genes greater than a twofold or less than twofold change in expression of S. aureus effected by subinhibitory concentrations of fusidic acid were found, including 232 up-regulated genes and 272 down-regulated genes, which were determined by transcriptome sequencing. Our results showed subinhibitory concentrations of fusidic acid significantly inhibited the expression of hla, spa, icaA, and cidA at the mRNA level in clinical S. aureus strains tested. And subinhibitory concentrations of fusidic acid can significantly reduce the hemolysis activity and α-toxin production of S. aureus. In addition, the subinhibitory concentrations of fusidic acid significantly inhibited biofilm formation, autolysis, cell aggregation, and polysaccharide intercellular adhesin (PIA) production of S. aureus. Moreover, fusidic acid effectively reduces the damage of mouse skin lesion area. Furthermore, fusidic acid reduced the expression of the two-component regulatory system saeRS and staphylococcal accessory gene regulator (sarA). In conclusion, our results suggested that the subinhibitory concentrations of fusidic acid may reduce the virulence of S. aureus by down-regulating sarA and saeRS to reduce biofilm formation and α-toxin expression, which will provide a theoretical basis for the clinical treatment of S. aureus infection. This is the first report that fusidic acid has an inhibitory effect on the virulence of S. aureus, and this broadens the clinical application of fusidic acid.
Highlights
Staphylococcus aureus is an important pathogen of humans, causing infections ranging from small skin infections to osteomyelitis, sepsis, and necrotizing pneumonia (Lowy, 1998)
To ensure that fusidic acid reduces the virulence of S. aureus by reducing the expression of virulence genes rather than reducing the amount of bacteria, we chose these three concentrations (1/16, 1/32, and 1/64 × minimum inhibitory concentration (MIC)), which did not affect the growth of two-component regulatory systems, and transcriptional regulation (Table 1)
Many studies have demonstrated that subinhibitory concentrations of antibiotics have an effect on S. aureus virulence factors (Otto et al, 2013) and biofilm formation (Majidpour et al, 2017)
Summary
Staphylococcus aureus is an important pathogen of humans, causing infections ranging from small skin infections to osteomyelitis, sepsis, and necrotizing pneumonia (Lowy, 1998). With the emergence of methicillin-resistant S. aureus (MRSA), the treatment of S. aureus infection has become one of the clinically difficult problems, and it is increasingly threatening the health of the public (Okesola, 2011) It is well-known that the production of toxins and the formation of biofilms are two important contributions to S. aureus infection. The α-toxin is 33.2 kDa of exocrine protein encoded by hla gene, which is a poreforming toxin that causes cell damage and death (Bhakdi and Tranum-Jensen, 1991). It has obvious hemolysis effects on red blood cells of various mammals, especially on rabbit red blood cells (Kebaier et al, 2012). If antibiotics can be used to reduce the production of S. aureus virulence factors and biofilm formation, it will greatly benefit the treatment of S. aureus infection
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