Repurposing Ponatinib Hydrochloride as an Antibacterial and Antibiofilm Agent Against Multidrug-Resistant Staphylococcus aureus

Abstract

With the continuous escalation of antimicrobial resistance, drug repurposing based on approved drugs has emerged as a promising strategy for the development of novel anti-infective agents. This study aimed to evaluate the antibacterial effect of the FDA-approved drug Ponatinib hydrochloride against multidrug-resistant S. aureus. Broth microdilution assay showed that ponatinib hydrochloride exhibited potent activity against Gram-positive bacteria, while the MICs against Gram-negative bacteria were all >100 μM. In addition, the MICs against 15 clinical multidrug-resistant S. aureus isolates ranged from 6.25 to 25 μM. Time-kill assay further revealed a pronounced concentration- and time-dependent bactericidal effect, with bacterial viability reduced to nearly the detection limit within 24 h at 4 × MIC. Anti-biofilm assays showed that ponatinib hydrochloride significantly inhibited S. aureus biofilm formation and disrupted mature biofilms. Moreover, serial passaging for 30 days did not induce an obvious increase in resistance. Mechanistic investigations demonstrated that ponatinib hydrochloride increased membrane permeability, induced intracellular reactive oxygen species (ROS) accumulation, and markedly reduced ATP levels. Finally, in a mouse infection model, ponatinib hydrochloride significantly improved the survival of infected mice, with a survival rate of 70% observed in the 15 mg/kg treatment group, while also reducing bacterial burdens and pro-inflammatory cytokine levels in tissues. Collectively, ponatinib hydrochloride exhibits potent antibacterial activity against multidrug-resistant S. aureus both in vitro and in vivo and represents a promising candidate for anti-MRSA therapy.