Molecular docking and proteomics reveals the synergistic antibacterial mechanism of theaflavin with β-lactam antibiotics against MRSA

Abstract

Recurrent epidemics of methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) have illustrated that the effectiveness of antibiotics in clinical application is rapidly fading. A feasible approach is to combine natural products with existing antibiotics to achieve an antibacterial effect. In this molecular docking study, we found that theaflavin (TF) preferentially binds the allosteric site of penicillin-binding protein 2a (PBP2a), inducing the PBP2a active site to open, which is convenient for β-lactam antibiotics to treat MRSA infection, instead of directly exerting antibacterial activity at the active site. Subsequent TMT-labeled proteomics analysis showed that TF treatment did not significantly change the landscape of the S. aureus USA300 proteome. Checkerboard dilution tests and kill curve assays were performed to validate the synergistic effect of TF and ceftiofur, and the fractional inhibitory concentration index (FICI) was 0.1875. The antibacterial effect of TF combined with ceftiofur was better than that of single-drug treatment in vitro. In addition, TF effectively enhanced the activity of ceftiofur in a mouse model of MRSA-induced pneumonia. Our findings provide a potential therapeutic strategy to combine existing antibiotics with natural products to resolve the prevalent infections of multidrug-resistant pathogens.

β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

“…A novel β-lactamase (Axc) with carbapenemase activity was identified through proteomics approach in a meropenem resistant clinical isolate of Achromobacter xylosoxidans (Fleurbaaij et al, 2018). Recently, Guan et al, had utilized proteomics to reveal synergistic action of theaflavin, a polyphenolic compound present in fermented tea with β-lactam antibiotics against MRSA (Guan et al, 2022). Cassiano et al, had recently utilized chemical proteomics guided approach to identify novel targets of the MBL inhibitor, magnolol (Cassiano et al, 2019).…”

Molecular docking, Dynamics and Experimental approach integrated identification of Phytopharmaceuticals against methicillin-resistant staphylococcus aureus (MRSA) infection

“…These are also tested against various bacterial strains under In-vitro conditions [AlSheikh HMA et al, 2020, Cheng W et al, 2023, Hatano T et al, 2003, Ekambaram SP et al, 2016. In recent years, molecular docking, dynamics, and network pharmacology have been widely used by researchers for evaluating the therapeutic mechanisms of various natural compounds against bacterial infections [Guan S et al, 2022, Masumi M et al, 2022, Pisano MB et al, 2019. Molecular docking is the computational approach that is used to analyse the interaction between the ligand and the protein molecule, whereas molecular dynamics simulation is used to assess the structural exibility and stability of the protein molecules in the presence of compounds [Morris GM et al, 2008].…”

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole

“…In recent years, various novel strains of multidrug-resistant bacteria have been continuously reported, like extended-spectrum β-Lactamases (ESBLs) and methicillin-resistant Staphylococcus aureus (MRSA). It is widely known that MRSA causes a range of infections in humans, such as necrotizing pneumonia, bacteremia, and endocarditis . Furthermore, a recent study has revealed the high prevalence of MRSA worldwide .…”

“…It is widely known that MRSA causes a range of infections in humans, such as necrotizing pneumonia, 3 bacteremia, and endocarditis. 4 Furthermore, a recent study has revealed the high prevalence of MRSA worldwide. 5 The emergence and rapid spread of MRSA have caused significant and serious infections in both animals and humans.…”