title: In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis.
abstract: The generation of a new antifungal against Candida albicans biofilms has become a major priority, since biofilm formation by this opportunistic pathogenic fungus is usually associated with an increased resistance to azole antifungal drugs and treatment failures. Miltefosine is an alkyl phospholipid with promising antifungal activity. Here, we report that, when tested under planktonic conditions, miltefosine displays potent in vitro activity against multiple fluconazole-susceptible and -resistant C. albicans clinical isolates, including isolates overexpressing efflux pumps and/or with well-characterized Erg11 mutations. Moreover, miltefosine inhibits C. albicans biofilm formation and displays activity against preformed biofilms. Serial passage experiments confirmed that miltefosine has a reduced potential to elicit resistance, and screening of a library of C. albicans transcription factor mutants provided additional insight into the activity of miltefosine against C. albicans growing under planktonic and biofilm conditions. Finally, we demonstrate the in vivo efficacy of topical treatment with miltefosine in the murine model of oropharyngeal candidiasis. Overall, our results confirm the potential of miltefosine as a promising antifungal drug candidate, in particular for the treatment of azole-resistant and biofilm-associated superficial candidiasis.
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Taissa Vieira Machado
authors.identifier: http://orcid.org/0000-0001-5600-4367
authors.initials: TV
authors.lastname: Vila
authors.affiliation: Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chaturvedi
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rozental
authors.affiliation: Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA jose.lopezribot@utsa.edu.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Lopez-Ribot
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D002180:Candidiasis, Oral / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics; D015725:Fluconazole / Q000494:pharmacology; D015870:Gene Expression; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010933:Plankton / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D014157:Transcription Factors; D010767:Phosphorylcholine; C039128:miltefosine; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System