Exploring the modulatory impact of isosakuranetin on Staphylococcus aureus : Inhibition of sortase A activity and α-haemolysin expression

Abstract

The ubiquity of methicillin-resistant Staphylococcus aureus (MRSA) and the mounting prevalence of antibiotic resistance necessitate the identification of novel therapeutic approaches to reduce the selective pressure of antibiotics. Targeting bacterial virulence factors, such as the pivotal Sortase A (SrtA) in S. aureus for adhesion and invasion, and the salient toxin α-Hemolysin (Hla), offers a sophisticated approach to attenuate pathogenicity without bacterial elimination. Herein, we report the discovery of a flavonoid, isosakuranetin, which inhibits the activity of S. aureus SrtA. A fluorescence resonance energy transfer assay revealed that isosakuranetin exhibited a low IC 50 of 21.20 μg/mL. Furthermore, isosakuranetin significantly inhibited SrtA-related virulence properties, such as bacterial adhesion to fibrinogen, biofilm formation, and invasion of A549 cells. We employed fluorescence quenching and molecular docking to determine the interactions between isosakuranetin and SrtA, revealing the key amino acid sites for binding. Importantly, isosakuranetin inhibited the haemolytic activity of S. aureus in vitro at a concentration of 32 μg/mL. Moreover, isosakuranetin effectively suppressed the transcription and expression of Hla in a dose-dependent manner and regulated the transcription of RNAIII , the upstream operator of Hla. Notably, isosakuranetin demonstrated in vivo efficacy in a mouse model of S. aureus -induced pneumonia by significantly improving survival rates and reducing lung damage. This is a valuable finding, as isosakuranetin’s dual inhibitory effects on SrtA and haemolytic activity, as well as its anti-virulence activity against MRSA, make it an excellent candidate for therapeutic development.

Exploring the multifaceted therapeutic mechanism of Schisanlactone E (XTS) in APP/PS1 mouse model of Alzheimer’s disease through multi-omics analysis

“…In metabolomic studies of gut and brain tissues, we found that XTS intervention markedly increased the levels of Isosakuranetin in the gut. Isosakuranetin has notable anti-inflammatory properties and has shown efficacy in a mouse model of pneumonia induced by Staphylococcus aureus ( Tian et al, 2023 ). Additionally, it reduces neurological damage in a rat model of cerebral infarction, demonstrating neuroprotective effects ( Janyou et al, 2024 ), and exhibits anti-nociceptive properties in a rat model of peripheral neuropathy ( Jia et al, 2017 ).…”

Unraveling the efficacy of verbascoside in thwarting MRSA pathogenicity by targeting sortase A

“…Finally, as a membrane-associated protein, SrtA is a relatively accessible target, as inhibitors do not need to traverse the bacterial outer membrane to enter the cytoplasm. To date, several SrtA inhibitors have been identified that are derived from various natural products, small organic molecules, and peptides (Tian et al 2022 ; Wang et al 2022 ; Tian et al 2023 ; Wang et al 2023 ). With their diverse, novel structures, rich biological activities, and minimal side effects, natural compounds have always been a primary choice in new drug development (Zhao et al 2022 ).…”