{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:21:38Z","timestamp":1791400898027,"version":"4.3.3"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Leishmania<\/jats:italic>\n                      spp., the causative agents of leishmaniasis, pose significant global health threats, with visceral leishmaniasis being the most severe and fatal form. The increasing drug resistance in the treatment of leishmaniasis emphasizes the urgent need for novel therapeutic approaches. One promising strategy involves targeting essential cellular mechanisms such as nutrient acquisition, particularly iron, which is critical for energy metabolism and signal transduction.\n                      <jats:italic toggle=\"yes\">Leishmania<\/jats:italic>\n                      spp. cannot synthesize heme\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      and rely on host-derived iron and heme for survival and pathogenicity. Gallium [Ga(III)] is an iron [Fe(III)]-mimetic molecule that has emerged as a promising antimicrobial agent, offering a novel approach to combat infections, mainly by replacing Fe(III) in redox enzymes thereby disrupting essential metabolic pathways and impairing microbial viability. In this study, the antiparasitic activity of Ga (III)-protoporphyrin IX (GaPPIX) was tested against\n                      <jats:italic toggle=\"yes\">Leishmania major<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Leishmania infantum<\/jats:italic>\n                      , both in promastigotes and intracellular amastigotes. Our results demonstrate that GaPPIX inhibits the viability of both species, specifically targeting the enzymatic activity of cytochrome\n                      <jats:italic toggle=\"yes\">c<\/jats:italic>\n                      oxidase, with a higher sensitivity observed in\n                      <jats:italic toggle=\"yes\">L. major<\/jats:italic>\n                      . The inhibitory effect is reversed by hemin, suggesting specificity for\n                      <jats:italic toggle=\"yes\">Leishmania<\/jats:italic>\n                      heme-dependent cellular processes and a possible cytostatic action. Moreover, we found that GaPPIX can effectively synergize with miltefosine. This feature, coupled with its minimal toxicity toward human cells, makes GaPPIX a good candidate to be potentially developed as a novel anti-\n                      <jats:italic toggle=\"yes\">Leismania<\/jats:italic>\n                      agent.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        This study is significant as it addresses a critical challenge in leishmaniasis management, namely, the increasing incidence of drug resistance and toxicity, compounded by the scarcity of effective therapeutic options. We demonstrate that GaPPIX, a heme-mimetic compound, exhibits potent antiparasitic activity against both\n                        <jats:italic toggle=\"yes\">Leishmania major<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">Leishmania infantum<\/jats:italic>\n                        , while displaying minimal cytotoxicity toward human cells, underscoring its potential as a safe and targeted therapeutic candidate. Importantly, the ability of GaPPIX to synergize with the first-line drug miltefosine highlights its translational relevance in combination therapies, which are essential for overcoming resistance and improving treatment efficacy. Collectively, these findings advance GaPPIX as a promising approach for the development of innovative therapeutics against a neglected but globally significant disease.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02118-25","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T14:00:39Z","timestamp":1769781639000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["<i>In vitro<\/i>\n                    activity of gallium-protoporphyrin IX against\n                    <i>Leishmania major<\/i>\n                    and\n                    <i>Leishmania infantum<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2849-6772","authenticated-orcid":false,"given":"Sara","family":"Maestrini","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04q4kt073","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo","place":["Urbino (PU), Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5456-1821","authenticated-orcid":true,"given":"Aurora","family":"Diotallevi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04q4kt073","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo","place":["Urbino (PU), Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0064-4610","authenticated-orcid":true,"given":"Sarah","family":"Hijazi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04q4kt073","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo","place":["Urbino (PU), Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Habouria","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04pwyer06","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Transmission, Control and Immunobiology of Infection, Institut Pasteur de Tunis","place":["Tunis, Tunisia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5619-7912","authenticated-orcid":true,"given":"Emanuela","family":"Frangipani","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04q4kt073","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo","place":["Urbino (PU), Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1747-526X","authenticated-orcid":true,"given":"Luca","family":"Galluzzi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04q4kt073","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomolecular Sciences, University of Urbino Carlo Bo","place":["Urbino (PU), Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31204-2"},{"key":"e_1_3_3_3_2","unstructured":"WHO. 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