Journal
TOXINS
Volume 10, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/toxins10100385
Keywords
sortase A; Staphylococcus aureus; erianin; inhibitor; molecular mechanism
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Funding
- Shuangzhi Project of Sichuan Agricultural University [03571444, 03572452]
- General Project of Sichuan Provincial Department of Education [16ZB0036]
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With continuous emergence and widespread of multidrug-resistant Staphylococcus aureus infections, common antibiotics have become ineffective in treating these infections in the clinical setting. Anti-virulence strategies could be novel, effective therapeutic strategies against drug-resistant bacterial infections. Sortase A (srtA), a transpeptidase in gram-positive bacteria, can anchor surface proteins that play a vital role in pathogenesis of these bacteria. SrtA is known as a potential antivirulent drug target to treat bacterial infections. In this study, we found that erianin, a natural bibenzyl compound, could inhibit the activity of srtA in vitro (half maximal inhibitory concentration-IC50 = 20.91 +/- 2.31 mu g/mL, 65.7 +/- 7.2 mu M) at subminimum inhibitory concentrations (minimum inhibitory concentrations-MIC = 512 mu g/mL against S. aureus). The molecular mechanism underlying the inhibition of srtA by erianin was identified using molecular dynamics simulation: erianin binds to srtA residues Ile182, Val193, Trp194, Arg197, and Ile199, forming a stable bond via hydrophobic interactions. In addition, the activities of S. aureus binding to fibronectin and biofilm formation were inhibited by erianin, when co-culture with S. aureus. In vivo, erianin could improve the survival in mice that infected with S. aureus by tail vein injection. Experimental results showed that erianin is a potential novel therapeutic compound against S. aureus infections via affecting srtA.
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