In order to successfully infect a host, S. aureus is a gram-positive bacterium that is capable of infecting numerous tissue types and has demonstrated a rapid ability to develop antibiotic resistance ( Lowy, 1998 Chambers and Deleo, 2009). aureus, including MRSA ( Salam and Quave, 2018 Tan et al., 2018 Wu et al., 2019). Indeed, the inhibition of virulence has been repeatedly cited and demonstrated in the literature as a promising anti-infective strategy against S. While many efforts are being made to discover and develop antibiotics that target new pathways, much research has also been devoted to targeting bacterial virulence as an alternative approach ( Alford et al., 2019 Fleitas Martínez et al., 2019). All currently approved antibiotic treatments exert their activity via bacteriostatic or bactericidal mechanisms ( Tyers and Wright, 2019). In the face of spreading antibiotic resistance, the world is in need of new anti-infective drugs ( Rello et al., 2019). aureus as one of its most threatening characteristics. Both organizations cite antibiotic resistance in S. aureus a high priority pathogen for which new antibiotics are urgently needed ( WHO, 2017 WHO, 2020). aureus, including MRSA, as a leading international pathogen of concern both in the community and in hospitals, and in 2017 it cited S. The World Health Organization (WHO) has designated S. aureus caused 323,700 hospitalizations, 10,600 deaths, and $1.7 billion in healthcare costs ( CDC, 2019). aureus as a “serious threat,” and in 2017 alone S. In 2019, the Centers for Disease Control and Prevention (CDC) labeled S. aureus (MRSA), remains a pathogen of great concern in the United States and across the world. Staphylococcus aureus, including methicillin-resistant S. The results establish 1 as a promising antivirulence candidate for development against MRSA. Finally, 1 reduced dermonecrosis in a murine model of MRSA infection.
Compound 1 did not inhibit biofilm production, and at high concentrations it exerted cytotoxicity against human keratinocytes greater than that of 224C-F2. It inhibited agr::P3 activation (IC 50 = 31.72 µM), δ-toxin production (IC 50 = 31.72 µM in NRS385), supernatant cytotoxicity to HaCaT human keratinocytes (IC 50 = 7.93 µM in NRS385), and rabbit erythrocyte hemolytic activity (IC 50 = 7.93 µM in LAC).
In a series of assays assessing inhibition of markers of MRSA virulence, 1 exerted activities in the low micromolar range. Isomers of 1 were also detected in an adjacent fraction. Its structure was established by nuclear magnetic resonance, mass spectrometry and X-ray diffraction analyses. Through further bioassay-guided fractionation using reverse-phase high performance liquid chromatography, a novel hydroperoxy cycloartane triterpenoid, castaneroxy A ( 1), was isolated.
The fraction demonstrated high activity in vitro and effective attenuation of MRSA pathogenicity in a mouse model of skin infection. In a follow-up of a study examining the MRSA quorum sensing inhibitory activity of extracts of Italian plants used in local traditional medicine, 224C-F2 was reported as a bioactive fraction of a Castanea sativa (European chestnut) leaf extract. The development of novel anti-infectives that inhibit quorum sensing and thus virulence in MRSA has been recurrently proposed as a promising therapeutic approach. The current arsenal of antibiotics works by targeting bacterial growth and survival, which exerts great selective pressure for the development of resistance. Methicillin-resistant Staphylococcus aureus (MRSA) represents one of the most serious infectious disease concerns worldwide, with the CDC labeling it a “serious threat” in 2019.