{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T03:39:47Z","timestamp":1776656387367,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,16]]},"group-title":"Microbiology","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,16]]},"abstract":"<jats:title>ABSTRACT<\/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 mutations in\n                  <jats:italic>FKS2<\/jats:italic>\n                  , which encodes a target of echinocandins and fungerps, cause large amounts of heteroresistance in\n                  <jats:italic>Candida glabrata<\/jats:italic>\n                  through heterogeneous expression of the gene even in clonal cell populations. Heteroresistance decreased when stress-responsive transcription factors (Crz1, Rlm1) were eliminated and was nearly abolished when the upstream regulators (calcineurin, Slt2) were mutated or inhibited. Identical gain-of-resistance mutations in\n                  <jats:italic>FKS1<\/jats:italic>\n                  , a paralog of\n                  <jats:italic>FKS2<\/jats:italic>\n                  , showed much less heteroresistance due to its constitutive expression coupled with variable levels of antagonism by wild-type\n                  <jats:italic>FKS2<\/jats:italic>\n                  . A genome-wide screen using Tn-seq revealed additional regulators of heteroresistance and resistance including\n                  <jats:italic>IRA1<\/jats:italic>\n                  , an inhibitor of the Ras1-PKA signaling pathway that senses glucose availability.\n                  <jats:italic>IRA1<\/jats:italic>\n                  increased expression of\n                  <jats:italic>FKS2<\/jats:italic>\n                  and decreased expression of\n                  <jats:italic>FKS1<\/jats:italic>\n                  , which increased heteroresistance and decreased resistance, respectively, when these genes carried resistance mutations. Similar principles may govern heteroresistance in other fungal pathogens such as\n                  <jats:italic>Candida parapsilosis<\/jats:italic>\n                  , which naturally carries resistance mutations in\n                  <jats:italic>FKS1<\/jats:italic>\n                  and frequently exhibits heteroresistance to echinocandins, and\n                  <jats:italic>Candidozyma auris<\/jats:italic>\n                  , which easily acquires such mutations.\n                <\/jats:p>","DOI":"10.64898\/2026.04.16.718912","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T03:35:13Z","timestamp":1776396913000},"source":"Crossref","is-referenced-by-count":0,"title":["A Mechanism Driving Echinocandin Heteroresistance in\n                  <i>Candida glabrata<\/i>"],"prefix":"10.64898","author":[{"given":"Abigail A.","family":"Harrington","sequence":"first","affiliation":[{"name":"Department of Biology, Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6877-6321","authenticated-orcid":false,"given":"Kyle W.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Department of Biology, Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041919551105000_2026.04.16.718912v1.1","doi-asserted-by":"crossref","unstructured":"Gold, J.A.W. , et al., Candida glabrata emerges as the most common cause of candidemia: analysis of a large hospital-based database, United States, 2016-2024. 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