Beyond antiparasitic activity: elucidating the antibacterial potency of pyrvinium pamoate.

UNLABELLED: 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 membrane-permeabilizing agents or in the presence of efflux pump inhibitors.

IMPORTANCE: Antimicrobial resistance is a growing global crisis that threatens the effectiveness of current treatments. Developing new antibiotics is challenging and time-consuming, so repurposing existing drugs offers a faster alternative. Pyrvinium pamoate (PP) is a well-known antiparasitic drug that has also been studied for cancer treatment, but its antibacterial potential has received little attention. In this study, we show that PP is effective in killing several gram-positive bacteria, including Staphylococcus aureus, at low doses. Although gram-negative bacteria are more resistant, we found that combining PP with agents that open up bacterial membranes makes these bacteria more vulnerable. Our research also explains how bacteria take in and remove PP, which can affect how well it works. These findings support the idea of repurposing PP as an antibiotic, especially in combination therapies, to help combat multidrug-resistant infections.