Abstract
The emergence of fungal “superbugs” resistant to the limited cohort of anti-fungal agents available to clinicians is eroding our ability to effectively treat infections by these virulent pathogens. As the threat of fungal infection is escalating worldwide, this dwindling response capacity is fueling concerns of impending global health emergencies. These developments underscore the urgent need for new classes of anti-fungal drugs and, therefore, the identification of new targets. Phosphoinositide signaling does not immediately appear to offer attractive targets due to its evolutionary conservation across the Eukaryota. However, recent evidence argues otherwise. Herein, we discuss the evidence identifying Sec14-like phosphatidylinositol transfer proteins (PITPs) as unexplored portals through which phosphoinositide signaling in virulent fungi can be chemically disrupted with exquisite selectivity. Recent identification of lead compounds that target fungal Sec14 proteins, derived from several distinct chemical scaffolds, reveals exciting inroads into the rational design of next generation Sec14 inhibitors. Development of appropriately refined next generation Sec14-directed inhibitors promises to expand the chemical weaponry available for deployment in the shifting field of engagement between fungal pathogens and their human hosts.
Highlights
The human population carries a remarkable load of commensal microorganisms that execute functions beneficial to the human host
We focus on future prospects for expanding the dwindling antifungal drug arsenal with primary emphasis on targeting phosphoinositide signaling, phosphatidylinositol transfer proteins (PITPs)-dependent phosphatidylinositol 4-phosphate [PtdIns(4)P] signaling in these pathogens
There are no Sec14-like proteins/domains expressed by mammals that carry a PtdCho-binding barcode—suggesting no mammalian Sec14-like protein will be inadvertently targeted by NPPM- or picolinamide-based inhibitors of fungal Sec14 PITPs
Summary
The human population carries a remarkable load of commensal microorganisms that execute functions beneficial to the human host. While superficial fungal infections in humans are commonplace, overgrowth of commensal fungi can develop into life-threatening systemic infections Such deep fungal invasions represent an escalating health problem worldwide and claim in excess of 1.5 million lives annually [3,4]. These diseases come with mortality rates surpassing those associated with many viral and bacterial infections [5]. We briefly discuss the current status of antifungal drug therapy and the urgent need for development of new tools for chemical intervention This urgency is fueled by the rapidly climbing incidence of human fungal diseases, coupled with the rise of multi-drug-resistant fungal pathogens. While the discussion focuses on Candida as infectious agent, these concepts translate to other fungal pathogens as well
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