Beyond antiparasitic activity: elucidating the antibacterial potency of pyrvinium pamoate

Abstract

Antimicrobial resistance represents a critical global health threat, demanding innovative therapeutic strategies. In this study, we investigate the repurposing potential of pyrvinium pamoate (PP)—a long-established anthelmintic agent—for antibacterial applications. Comprehensive in vitro analyses revealed that while gram-negative bacteria exhibited inherent resistance due to limited drug uptake, gram-positive pathogens, particularly within the orders Actinomycetales and Bacillales, were markedly susceptible at low micromolar concentrations. Enhanced antibacterial efficacy was observed when PP was combined with outer membrane-permeabilizing agents, such as the peptide D11 or pentamidine, which facilitated increased intracellular accumulation. Additionally, the role of efflux pump activity was explored; its inhibition in Staphylococcus aureus resulted in significant drug retention and a concomitant reduction in minimum inhibitory concentrations, while disruption of the proton motive force attenuated uptake. The compound demonstrated bactericidal effects against S. aureus and a bacteriostatic profile against Pseudomonas aeruginosa when sensitized with outer membrane permeabilizing agents. Furthermore, synergistic studies with several antibiotics revealed the potential of PP as a valuable addition to the antimicrobial arsenal against multidrug-resistant pathogens. These findings motivate further mechanistic studies and clinical evaluation of PP in antimicrobial therapy. PP shows promise as a repurposed antibacterial agent, particularly against gram-positive pathogens, with enhanced activity against gram-negative pathogens when combined with membranepermeabilizing agents or in the presence of efflux pump inhibitors.