Milbemycins: more than efflux inhibitors for fungal pathogens
| Autor: | Patrick Vandeputte, Maurizio Sanguinetti, Bertrand Rochat, Luis Vale Silva, Dominique Sanglard, Riccardo Torelli |
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| Přispěvatelé: | Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA) |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Azoles
Antifungal Agents [SDV]Life Sciences [q-bio] Drug Resistance ATP-binding cassette transporter Candida glabrata Drug resistance Mice Gene Expression Regulation Fungal Oximes Pharmacology (medical) Candida albicans Fluconazole Inbred BALB C Anthelmintics 0303 health sciences Mice Inbred BALB C biology Candidiasis Corpus albicans Infectious Diseases Fungal Female Efflux Macrolides medicine.drug Genes Fungal Microbial Sensitivity Tests Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA Microbiology 03 medical and health sciences Drug Resistance Fungal medicine Animals Mechanisms of Action: Physiological Effects 030304 developmental biology Pharmacology 030306 microbiology Gene Expression Profiling Membrane Transport Proteins biology.organism_classification Protein ubiquitination Gene Expression Regulation Genes ATP-Binding Cassette Transporters candida albicans Reactive Oxygen Species Milbemycins |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2013, 57 (2), pp.873-386. ⟨10.1128/AAC.02040-12⟩ |
| ISSN: | 0066-4804 1098-6596 |
| DOI: | 10.1128/AAC.02040-12⟩ |
| Popis: | Existing antifungal agents are still confronted to activities limited to specific fungal species and to the development of resistance. Several improvements are possible either by tackling and overcoming resistance or exacerbating the activity of existing antifungal agents. In Candida glabrata , azole resistance is almost exclusively mediated by ABC transporters (including C. glabrata CDR1 [ CgCDR1 ] and CgCDR2 ) via gain-of-function mutations in the transcriptional activator CgPDR1 or by mitochondrial dysfunctions. We also observed that azole resistance was correlating with increasing virulence and fitness of C. glabrata 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 C. glabrata . 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 C. glabrata efflux with the highest activity for A3 oxim below 1 μg/ml. More surprising was that oxim derivatives had intrinsic fungicidal activity above 3.2 μg/ml, thus highlighting effects additional to the efflux inhibition. Similar values were obtained with C. albicans . Our data show that the fungicidal activity could be related to reactive oxygen species formation in these species. Transcriptional analysis performed both in C. glabrata and C. albicans 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 Candida species. In azole-resistant isolates, oxims acted synergistically in vivo 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 C. glabrata and C. albicans . |
| Databáze: | OpenAIRE |
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