{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:49:18Z","timestamp":1791474558861,"version":"4.3.4"},"reference-count":70,"publisher":"American Society for Microbiology","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AI153414"],"award-info":[{"award-number":["R01-AI153414"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21-AI199177"],"award-info":[{"award-number":["R21-AI199177"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      While pathogenic fungi can acquire resistance to the current arsenal of antifungals through genetic mutations, heteroresistance has emerged as an important new cause of therapeutic failures. Heteroresistance is generally thought to arise in small subpopulations that display phenotypic resistance to antifungals without genetic mutations. This study blurs that line by showing gain-of-resistance (GOR) mutations in\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      , which encodes a target of echinocandins and fungerps, causing broad heteroresistance in\n                      <jats:italic toggle=\"yes\">Candida glabrata<\/jats:italic>\n                      . Identical gain-of-resistance mutations in\n                      <jats:italic toggle=\"yes\">FKS1<\/jats:italic>\n                      , a paralog of\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      , caused resistance and little or no heteroresistance. Heteroresistance of\n                      <jats:italic toggle=\"yes\">FKS2-GOR<\/jats:italic>\n                      strains decreased when stress-responsive transcription factors (Crz1 and Rlm1) known to increase\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      expression were eliminated and was nearly abolished when the upstream regulators (calcineurin and Slt2) were mutated or inhibited. Conversely, stresses and mutations known to increase\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      expression also increased the survival of\n                      <jats:italic toggle=\"yes\">FKS2-GOR<\/jats:italic>\n                      mutants exposed to high doses of echinocandins. A genome-wide screen using transposon sequencing revealed additional regulators of heteroresistance and resistance. Mutants lacking\n                      <jats:italic toggle=\"yes\">DFG5<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">SSK2<\/jats:italic>\n                      exhibited strongly increased\n                      <jats:italic toggle=\"yes\">FKS2-GOR<\/jats:italic>\n                      function without increased expression. Mutants lacking\n                      <jats:italic toggle=\"yes\">IRA1<\/jats:italic>\n                      , an inhibitor of the Ras1-PKA signaling pathway that senses glucose availability, decreased expression of\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      and increased expression of\n                      <jats:italic toggle=\"yes\">FKS1<\/jats:italic>\n                      , thereby decreasing heteroresistance and increasing resistance, respectively, when these genes carried GOR mutations. The findings suggest that heterogeneous expression of resistance genes and heterogeneous regulation of their products combine to produce echinocandin heteroresistance. Analogous mechanisms may facilitate heteroresistance to azoles and echinocandins in other\n                      <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                      species.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00549-26","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:49:56Z","timestamp":1791470996000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A gene network regulating echinocandin heteroresistance in\n                    <i>Candida glabrata<\/i>"],"prefix":"10.1128","author":[{"given":"Abigail A.","family":"Harrington","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Johns Hopkins University","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6877-6321","authenticated-orcid":true,"given":"Kyle W.","family":"Cunningham","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Johns Hopkins University","place":["Baltimore, 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