Phospholipid biosynthesis disruption renders the yeast cells sensitive to antifungals

Kundu, Deepika; Hameed, Saif; Fatima, Zeeshan; Pasrija, Ritu

doi:10.1007/s12223-019-00713-3

“…In addition to mediating azole efflux, Cdr1-3 are general phospholipid translocators in C. albicans and actively contribute to the biogenesis of the plasma membrane lipid bilayer, therefore influencing membrane integrity and phospholipid signaling ( 69 ). It is noteworthy that disruption of phospholipid homeostasis affects FLC susceptibility ( 70 ). The fact that both ergosterol and sphingolipids are essential for the correct localization of Cdr1 to lipid rafts in C. albicans adds further complexity to ascribing a role for Cdr1 in FLC resistance ( 71 , 72 ).…”

Section: Resultsmentioning

confidence: 99%

Small molecules restore azole activity against drug-tolerant and drug-resistant Candida isolates

Alabi,

Gautier,

Murphy

et al. 2023

mBio

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Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic Candida species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of Candida albicans , as evidenced by 100–1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of C. albicans and in other pathogenic Candida species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to C. albicans in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a Galleria mellonella model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., Candida auris ), as well as increased antifungal drug resistance. Among human fungal pathogens, Candida species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant Candida isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a Galleria mellonella model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.

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“…In addition to mediating azole efflux, Cdr1-3 are general phospholipid translocators in C. albicans and actively contribute to the biogenesis of the plasma membrane lipid bilayer, therefore influencing membrane integrity and phospholipid signaling (68). It is noteworthy that disruption of phospholipid homeostasis affects FLC susceptibility (69). The fact that both ergosterol and sphingolipids are essential for the correct localization of Cdr1 to lipid rafts in C. albicans adds further complexity to ascribing a role for Cdr1 in FLC resistance (70, 71).…”

Section: Resultsmentioning

confidence: 99%

Small Molecules Restore Azole Activity Against Drug-Tolerant and Drug-ResistantCandidaIsolates

Alabi

¹

,

Gautier

²

,

Murphy

³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug resistant species necessitate the development of new therapies. One strategy for combating drug resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic Candida species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of Candida albicans, as evidenced by 100-1000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of C. albicans and in other pathogenic Candida species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other antifungal drugs. A remarkable feature of the potentiation was that the combination of the 1,4-benzodiazepines with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to C. albicans in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of 1,4-benzodiazepines and fluconazole significantly enhanced host survival in a Galleria mellonella model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency.

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“…Membrane sphingolipid–ergosterol interactions are required for azole resistance . Various studies have confirmed that the action of azole drugs can be modulated by subtle modification of the plasma membrane lipid composition (Khandelwal et al ., 2018; Kundu et al ., 2020; Suchodolski et al ., 2020). Some clinical azole‐resistant isolates of pathogenic fungi exhibit altered plasma membrane lipid composition (Mishra et al ., 2008; Eddouzi et al ., 2013; Hull et al ., 2012).…”

Section: Role Of Fungal Sphingolipid Synthesis In Azole Resistancementioning

confidence: 99%

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

Song

¹

,

Xiao

²

,

Li

³

2020

Molecular Microbiology

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In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review describes evidence about the roles of sphingolipids in azole resistance and fungal virulence. Sphingolipids can serve as signaling molecules that contribute to azole resistance through modulation of the expression of drug efflux pumps. They also contribute to azole resistance by participating in various microbial pathways such as the unfolded protein response (UPR), pH-responsive Rim pathway, and pleiotropic drug resistance (PDR) pathway. In addition, sphingolipid signaling and eisosomes also coordinately regulate sphingolipid biosynthesis in response to azole-induced membrane stress. Sphingolipids are important for fungal virulence, playing roles during growth in hosts under stressful conditions, maintenance of cell wall integrity, biofilm formation, and production of various virulence factors. Finally, we discuss the possibility of exploiting fungal sphingolipids for the development of new therapeutic strategies to treat infections caused by pathogenic fungi.

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Phospholipid biosynthesis disruption renders the yeast cells sensitive to antifungals

Cited by 6 publications

References 50 publications

Small molecules restore azole activity against drug-tolerant and drug-resistant Candida isolates

Small molecules restore azole activity against drug-tolerant and drug-resistant Candida isolates

Small Molecules Restore Azole Activity Against Drug-Tolerant and Drug-ResistantCandidaIsolates

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

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