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Isoliquiritigenin Attenuates Staphylococcus aureus Adhesion and Invasion to Counteract Staphylococcus aureus
Lili Tian1,2, Jian Sun3, Hong Jiang1,2
1College of Animal Science and Veterinary Medicine (Affiliated Animal Hospital), Jinzhou Medical University, Jinzhou, Liaoning, China.
Introduction:
Methicillin-resistant Staphylococcus aureus (MRSA) is a major clinical challenge due to its virulence and multidrug resistance. Antivirulence strategies targeting key pathogenic mechanisms without affecting bacterial viability provide a promising alternative to conventional antibiotics.
Methods:
The inhibitory effect of isoliquiritigenin (ISL) on S. aureus sortase A (SrtA) was assessed using a fluorescence resonance energy transfer assay. Fluorescence quenching and molecular docking analyses were performed to elucidate the binding interaction between ISL and SrtA. Adhesion and biofilm formation were evaluated on fibrinogen- and fibronectin-coated surfaces, and bacterial growth was monitored to confirm non-bactericidal activity. The therapeutic efficacy of ISL was further examined in a murine pneumonia model through bacterial load quantification, histopathological analysis, and survival evaluation.
Results:
ISL inhibited SrtA activity in a dose-dependent manner (IC50 = 13.34 µg/mL), disrupted adhesion and biofilm formation without affecting bacterial growth, and bound reversibly to key catalytic residues of SrtA. In vivo, ISL treatment significantly reduced pulmonary bacterial burden, alleviated tissue damage, and improved survival in infected mice.
Discussion:
ISL effectively attenuates MRSA pathogenicity by targeting SrtA-mediated virulence rather than bacterial viability. These results highlight ISL as a promising antivirulence agent and a potential adjuvant for combating antibiotic-resistant S. aureus infections.
Insights
Isoliquiritigenin (ISL) inhibits methicillin-resistant Staphylococcus aureus (MRSA) virulence by targeting sortase A (SrtA). This promising antivirulence strategy reduces MRSA pathogenicity and improves survival in mouse models.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) presents a significant clinical challenge due to its high virulence and resistance to multiple antibiotics.
- Antivirulence strategies offer a novel therapeutic approach by targeting essential pathogenic mechanisms without promoting resistance.
Purpose of the Study:
- To investigate the antivirulence potential of isoliquiritigenin (ISL) against MRSA.
- To elucidate the mechanism of action of ISL, specifically its effect on Sortase A (SrtA) and bacterial adhesion/biofilm formation.
Main Methods:
- In vitro assays were used to assess ISL's inhibitory effect on SrtA activity, its binding interaction with SrtA via fluorescence quenching and molecular docking.
- Adhesion and biofilm formation assays were conducted on various surfaces, alongside bacterial growth monitoring to confirm non-bactericidal activity.
- In vivo efficacy was evaluated in a murine pneumonia model, assessing bacterial load, histopathology, and survival rates.
Main Results:
- ISL demonstrated dose-dependent inhibition of SrtA activity (IC50 = 13.34 µg/mL) and reversibly bound to key catalytic residues.
- ISL significantly disrupted bacterial adhesion and biofilm formation without impacting bacterial viability.
- In vivo studies showed ISL treatment reduced pulmonary bacterial burden, mitigated tissue damage, and improved survival in infected mice.
Conclusions:
- Isoliquiritigenin effectively attenuates MRSA pathogenicity by targeting SrtA-mediated virulence, not bacterial viability.
- ISL represents a promising antivirulence agent and a potential adjuvant therapy for combating antibiotic-resistant Staphylococcus aureus infections.
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