Drug Repurposing of Antihistamines as Antibiotic Adjuvants to Inhibit Biofilm Formation in Methicillin-Resistant Staphylococcus aureus: An In Silico and In Vitro Approach

Abstract

Methicillin-Resistant Staphylococcus aureus is an opportunistic pathogen that remains a serious threat to human health due to its high virulence, antibiotic resistance, and strong ability to form biofilms. Biofilm formation reduces the susceptibility of bacteria to conventional therapies and plays a critical role in persistent chronic infections. Drugs repurposing using antihistamines offers an efficient strategy to identify antibiotic adjuvants that can enhance antibiofilm efficacy. This study evaluates the potential of antihistamines, specifically fexofenadine, as an antibiotic adjuvant against biofilm-forming MRSA using integrated in silico and in vitro approaches. Molecular docking analysis targeting the biofilm regulator proteins AgrA (PDB ID: 4G4K) and SarA (PDB ID: 2FRH) showed that fexofenadine has high binding affinity, forming strong hydrogen and non-covalent interactions, and maintaining a stable complex during molecular dynamics simulations. In vitro checkerboard assay showed a synergistic effect between 0.5 µg/mL fexofenadine and 0.5 µg/mL cefoxitin, reducing planktonic bacterial growth by approximately 70% compared to the control. In the biofilm assay, the combination of fexofenadine 1 µg/mL and cefoxitin 16 µg/mL significantly inhibited biofilm formation by 70%, as indicated by lighter crystal violet staining. The in-silico results suggest that fexofenadine may interact with the biofilm regulatory proteins AgrA and SarA, which are anticipated to be involved in the quorum sensing system of Staphylococus aureus, while in vitro findings confirm its synergistic antibiofilm activity with cefoxitin. Overall, this study highlights the potential repurposing of antihistamines, particularly fexofenadine as an antibiofilm combination strategy to enhance therapeutic efficacy against antibiotic-resistant S.aureus infections. HIGHLIGHTS Antihistamine repurposing as a cefoxitin adjuvant against MRSA using in silico and in vitro Molecular docking shows fexofenadine has high binding affinity to AgrA −6.9 and SarA −6.2 kcal/mol, with stable interactions confirmed by molecular dynamics, indicating its contribution as a cefoxitin adjuvant in antibiofilm therapy Fexofenadine combined with cefoxitin reduces planktonic growth and biofilm formation by 10% GRAPHICAL ABSTRACT

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