Enhanced Efflux Pump Expression in Candida Mutants Results in Decreased Manogepix Susceptibility

Abstract

Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix susceptibility. In C. albicans, a gain-of-function mutation in the transcription factor gene ZCF29 activated expression of ATP-binding cassette transporter genes CDR11 and SNQ2. In C. parapsilosis, a mitochondrial deletion activated expression of the major facilitator superfamily transporter gene MDR1.

New Antimycotics in the Pipeline – For Ophthalmology Too?

“…▪ Regarding 4. Some fungi have an efflux pump similar to that found in bacteria [37,38]. To overload this pump, high dosing is needed.…”

“…In [36] sind die MG dargestellt und weitere Therapiehinweise aufgeführt. ▪ Ad 4: Ähnlich wie Bakterien können auch manche Pilze eine "efflux pump" haben [37,38]. Um diese zu überlasten, gilt die Devise "nicht kleckern, sondern klotzen".…”

Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections

“…Two C. parapsilosis and C. albicans mutants were identified that demonstrated 4- to 8-fold decreased susceptibility to MGX in which the gwt1 gene sequence was similar to the wild-type [ 42 ]. These mutants were further investigated and the change in MIC was determined to be efflux-mediated [ 49 ]. The C. parapsilosis mutant contained a mitochondrial deletion, which activated expression of the major facilitator superfamily transporter gene MDR1 .…”

“…The C. albicans mutant demonstrated a gain-of-function mutation in the transcription factor gene ZCF29 , which activated expression of the ATP-binding cassette transporter genes CDR11 and SNQ2 . These two mutants also showed 2- and 4-fold decreased susceptibility to FLC, but not AMB or CAS [ 42 , 49 ]. These data are consistent with the observation that a subset of FLC resistant mutations in several species may lead to small increases in MGX MIC values [ 50 ].…”

“…These data are consistent with the hypothesis of a linkage between MGX and FLC MIC values in a small subset FLC-resistant strains. These data may be explained by the analysis of laboratory generated mutants in which some isolates with efflux related mutations displayed a 4- to 8-fold increase in the MIC of MGX and a concomitant 2- to 4-fold increase in the FLC MIC [ 49 ]. This is in contrast to target-based Gwt1 mutants in which increased MIC values for MGX, but not FLC, were observed [ 42 ].…”