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In<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida glabrata<\/jats:named-content>, azole resistance is almost exclusively mediated by ABC transporters (including<jats:italic>C. glabrata CDR1<\/jats:italic>[<jats:italic>CgCDR1<\/jats:italic>] and<jats:italic>CgCDR2<\/jats:italic>) via gain-of-function mutations in the transcriptional activator<jats:italic>CgPDR1<\/jats:italic>or by mitochondrial dysfunctions. We also observed that azole resistance was correlating with increasing virulence and fitness of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. glabrata<\/jats:named-content>in animal models of infection. This observation motivated the re-exploitation of ABC transporter inhibitors as a possible therapeutic intervention to decrease not only the development of azole resistance but also to interfere with the virulence of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. glabrata<\/jats:named-content>. Milbemycins are known ABC transporter inhibitors, and here we used commercially available milbemycin A3\/A4 oxim derivatives to verify this effect. As expected, the derivatives were inhibiting<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. glabrata<\/jats:named-content>efflux with the highest activity for A3 oxim below 1 \u03bcg\/ml. More surprising was that oxim derivatives had intrinsic fungicidal activity above 3.2 \u03bcg\/ml, thus highlighting effects additional to the efflux inhibition. Similar values were obtained with<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>. Our data show that the fungicidal activity could be related to reactive oxygen species formation in these species. Transcriptional analysis performed both in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. glabrata<\/jats:named-content>and<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>exposed to A3 oxim highlighted a core of commonly regulated genes involved in stress responses, including genes involved in oxidoreductive processes, protein ubiquitination, and vesicle trafficking, as well as mitogen-activated protein kinases. However, the transcript profiles contained also species-specific signatures. Following these observations, experimental treatments of invasive infections were performed in mice treated with the commercial A3\/A4 oxim preparation alone or in combination with fluconazole. Tissue burden analysis revealed that oxims on their own were able to decrease fungal burdens in both<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida<\/jats:named-content>species. In azole-resistant isolates, oxims acted synergistically<jats:italic>in vivo<\/jats:italic>with fluconazole to reduce fungal burden to levels of azole-susceptible isolates. In conclusion, we show here the potential of milbemycins not only as drug efflux inhibitors but also as effective fungal growth inhibitors in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. glabrata<\/jats:named-content>and<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>.<\/jats:p>","DOI":"10.1128\/aac.02040-12","type":"journal-article","created":{"date-parts":[[2012,12,4]],"date-time":"2012-12-04T14:01:14Z","timestamp":1354629674000},"page":"873-886","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["Milbemycins: More than Efflux Inhibitors for Fungal Pathogens"],"prefix":"10.1128","volume":"57","author":[{"given":"Luis Vale","family":"Silva","sequence":"first","affiliation":[{"name":"Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Sanguinetti","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Vandeputte","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland"},{"name":"Groupe d'Etude des Interactions H\u00f4te-Pathog\u00e8ne, UPRES-EA 3142, Universit\u00e8 d'Angers, Centre Hospitalier Universitaire, Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Torelli","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, Universit\u00e0 Cattolica del Sacro Cuore, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Rochat","sequence":"additional","affiliation":[{"name":"Quantitative Mass Spectrometry Facility, University of Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Sanglard","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1567-1364.2009.00578.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2011.11.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00937-12"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01283-12"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00045-10"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.11.2753"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.4.1174-1183.2001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2008.06143.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000268"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1384-1392.2006"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05235.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00535-10"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00073-10"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.3.6.1639-1652.2004"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00069-09"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2008.06309.x"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01102-09"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00995-10"},{"key":"e_1_3_3_20_2","first-page":"234","article-title":"Seeking antifungal drug synergies","volume":"7","author":"Whiteway M","year":"2012","unstructured":"WhitewayM. 2012. 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