Roles for stress response and cell wall biosynthesis pathways in caspofungin tolerance in Cryptococcus neoformans

BioRxiv : the Preprint Server for Biology
Kaila M PianaltoJ Andrew Alspaugh

Abstract

Limited antifungal diversity and availability are growing problems for the treatment of fungal infections in the face of increasing drug resistance. The echinocandins, one of the newest classes of antifungal drugs, inhibit production of a crucial cell wall component. However, these compounds do not effectively inhibit the growth of the opportunistic fungal pathogen Cryptococcus neoformans , despite potent inhibition of the target enzyme. We therefore performed a forward genetic screen to identify cellular processes that mediate the relative tolerance of this organism to the echinocandin drug, caspofungin. Through these studies, we identified 14 genetic mutants that enhance caspofungin antifungal activity. Rather than directly affecting caspofungin antifungal activity, these mutations seem to prevent the activation of various stress-induced compensatory cellular processes. For example, the pfa4 Δ mutant has defects in the palmitoylation and localization of many of its target proteins, including the Ras GTPase and the Chs3 chitin synthase which are both required for caspofungin tolerance. Similarly, we have confirmed the link between caspofungin treatment and calcineurin signaling in this organism, but we suggest a deeper mechani...Continue Reading

Related Concepts

Antifungal Agents
Cell Wall
Chitin Synthase
Cryptococcus neoformans
Drug Resistance
Face
Guanosine Triphosphate Phosphohydrolases
Immune Tolerance
Mycoses
Biological Adaptation to Stress

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.