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In this study, we investigate the repurposing potential of pyrvinium pamoate (PP)\u2014a long-established anthelmintic agent\u2014for antibacterial applications. Comprehensive\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      analyses revealed that while gram-negative bacteria exhibited inherent resistance due to limited drug uptake, gram-positive pathogens, particularly within the orders\n                      <jats:italic toggle=\"yes\">Actinomycetales<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Bacillales<\/jats:italic>\n                      , 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\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      and a bacteriostatic profile against\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      , 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02158-25","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T12:06:51Z","timestamp":1759234011000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Beyond antiparasitic activity: elucidating the antibacterial potency of pyrvinium pamoate"],"prefix":"10.1128","volume":"13","author":[{"given":"Angela","family":"Alcaraz-Mart\u00ednez","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/026yy9j15","id-type":"ROR","asserted-by":"publisher"}],"name":"Departamento de Microbiolog\u00eda Cl\u00ednica, Instituto de Investigaci\u00f3n Biosanitaria ibs. 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