{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:40:43Z","timestamp":1792510843460,"version":"4.5.0"},"reference-count":65,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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":[[2026,10,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Invasive infections caused by\n                      <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                      spp. are associated with high morbidity and mortality, particularly in immunocompromised patients, and are increasingly difficult to treat due to rising antifungal resistance. In this work, we further investigate the antifungal properties of a previously reported nickel N-heterocyclic biscarbene derived from caffeine (compound 5) and describe the synthesis of an analogous nickel N-heterocyclic biscarbene based on benzimidazole (compound 8), designed to evaluate the impact of the biscarbene and xanthine frameworks on activity and toxicity. Compound 5 displayed selective activity against\n                      <jats:italic toggle=\"yes\">Nakaseomyces glabratus<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Candida glabrata<\/jats:italic>\n                      ), inhibited biofilm formation, and showed greater cellular accumulation in this species. In a\n                      <jats:italic toggle=\"yes\">Galleria mellonella<\/jats:italic>\n                      infection model, compound 5 significantly reduced fungal burden while exhibiting lower cytotoxicity than the benzimidazole analog. Importantly, although compound 5 and fluconazole are individually fungistatic, their combination was fungicidal against\n                      <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                      . In the presence of compound 5, the minimal inhibitory concentration of fluconazole decreased against both a fluconazole-resistant petite mutant and a respiratory-competent\n                      <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                      strain evolved\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      to fluconazole resistance. Compound 5 increased the frequency of petite mutants, suggesting an effect on mitochondrial function; however, its retained activity against these mutants and its synergism with fluconazole in the petite background indicate an additional mechanism of action. These findings identify compound 5 as a promising antifungal adjuvant.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Invasive infections caused by\n                        <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                        are increasingly hard to treat because this pathogen is often tolerant to azoles and is developing resistance to echinocandins, leaving clinicians with few effective options. Our work explores a nickel\u2013caffeine complex that shows selective activity against\n                        <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                        and low toxicity, features that make it attractive as a promising candidate for further preclinical evaluation. Notably, this compound enhances the activity of fluconazole, turning a commonly used fungistatic drug into a fungicidal combination against both susceptible and resistant\n                        <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                        . By also affecting mitochondrial function yet remaining active in respiratory-deficient mutants, the compound appears to act through mechanisms distinct from existing antifungals. These properties suggest that metal-based xanthine complexes could be developed as adjuvants to enhance azole efficacy against difficult-to-treat\n                        <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                        infections, addressing an important priority identified for fungal pathogens.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00759-26","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T16:45:17Z","timestamp":1788367517000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A nickel N-heterocyclic biscarbene complex derived from caffeine enhances fluconazole efficacy against\n                    <i>Nakaseomyces glabratus<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-9351","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Malta-Lu\u00eds","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Romeo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Francescato","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Mariano","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalila","family":"Mil-Homens","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3296-1522","authenticated-orcid":false,"given":"Ana","family":"Petronilho","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5158-6414","authenticated-orcid":true,"given":"Catarina","family":"Pimentel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xankh89","id-type":"ROR","asserted-by":"publisher"}],"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa","place":["Oeiras, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.26"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00720-1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2016.11.019"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01611-0"},{"key":"e_1_3_4_6_2","unstructured":"WHO. 2022. 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