Evaluating the scope of rural general surgery in British Columbia.

BACKGROUND: Rural general surgeons perform many procedures outside the conventional scope of the specialty. Unique to British Columbia, the Rural Practice Subsidiary Agreement (RSA) formally defines rurality in the province. Our goal is to understand the scope of practice for BC's rural general surgeons and whether it has been affected over time by changing privileging guidelines. METHODS: Medical Services Plan (MSP) data were collected from 2011 to 2021 for procedures billed by general surgeons in communities defined by the RSA as rural. We categorized codes from the MSP based on surgical specialty. For each community, we calculated the totals for these categories considering what other surgical specialties were present as well as changes over time. RESULTS: From 2011 to 2021, 222 905 procedures were performed in 23 rural communities in BC. Colonoscopies were the most frequently performed procedure (n = 80 114, 35.9%), followed by colorectal (n = 23 891, 10.7%) and hernia procedures (n = 20 911, 9.4%). The most common unconventional procedures were plastic surgeries (n = 8077, 3.6%). Classification within the RSA did not significantly influence the percentage of unconventional general surgery procedures performed (p = 0.4). When another surgical specialty was present, there was often a decrease in the number of that specialty's procedures performed by general surgeons. Over the past decade, rural general surgeons performed fewer unconventional general surgery procedures (p < 0.001). CONCLUSION: General surgeons working in rural communities perform a variety of procedures based on resources, community need, and access to other specialists. Over the last decade, this appears to have been influenced by new privileging guidelines. Understanding the scope of rural general surgery can inform training opportunities and, as there is a migration away from rural surgeons performing as many unconventional procedures, can elucidate the implications on patients and communities.

Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-ß-thiophenylacrylamides exerts highly selective antifungal activity.

Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-ß-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth. NP-BTA was hypothesized to target C. albicans glutaminyl-tRNA synthetase, Gln4. Here, we confirmed through in vitro amino-acylation assays NP-BTA is a potent inhibitor of Gln4, and we defined how NP-BTA arrests Gln4's transferase activity using co-crystallography. This analysis also uncovered Met496 as a critical residue for the compound's species-selective target engagement and potency. Structure-activity relationship (SAR) studies demonstrated the NP-BTA scaffold is subject to oxidative and non-oxidative metabolism, making it unsuitable for systemic administration. In a mouse dermatomycosis model, however, topical application of the compound provided significant therapeutic benefit. This work expands the repertoire of antifungal protein synthesis target mechanisms and provides a path to develop Gln4 inhibitors.

A chemical screen identifies structurally diverse metal chelators with activity against the fungal pathogen Candida albicans.

Candida albicans, one of the most prevalent human fungal pathogens, causes diverse diseases extending from superficial infections to deadly systemic mycoses. Currently, only three major classes of antifungal drugs are available to treat systemic infections: azoles, polyenes, and echinocandins. Alarmingly, the efficacy of these antifungals against C. albicans is hindered both by basal tolerance toward the drugs and the development of resistance mechanisms such as alterations of the drug's target, modulation of stress responses, and overexpression of efflux pumps. Thus, the need to identify novel antifungal strategies is dire. To address this challenge, we screened 3,049 structurally-diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library against a C. albicans clinical isolate and identified 17 molecules that inhibited C. albicans growth by >80% relative to controls. Among the most potent compounds were CMLD013360, CMLD012661, and CMLD012693, molecules representing two distinct chemical scaffolds, including 3-hydroxyquinolinones and a xanthone natural product. Based on structural insights, CMLD013360, CMLD012661, and CMLD012693 were hypothesized to exert antifungal activity through metal chelation. Follow-up investigations revealed all three compounds exerted antifungal activity against non-albicans Candida, including Candida auris and Candida glabrata, with the xanthone natural product CMLD013360 also displaying activity against the pathogenic mould Aspergillus fumigatus. Media supplementation with metallonutrients, namely ferric or ferrous iron, rescued C. albicans growth, confirming these compounds act as metal chelators. Thus, this work identifies and characterizes two chemical scaffolds that chelate iron to inhibit the growth of the clinically relevant fungal pathogen C. albicansIMPORTANCEThe worldwide incidence of invasive fungal infections is increasing at an alarming rate. Systemic candidiasis caused by the opportunistic pathogen Candida albicans is the most common cause of life-threatening fungal infection. However, due to the limited number of antifungal drug classes available and the rise of antifungal resistance, an urgent need exists for the identification of novel treatments. By screening a compound collection from the Boston University Center for Molecular Discovery (BU-CMD), we identified three compounds representing two distinct chemical scaffolds that displayed activity against C. albicans. Follow-up analyses confirmed these molecules were also active against other pathogenic fungal species including Candida auris and Aspergillus fumigatus. Finally, we determined that these compounds inhibit the growth of C. albicans in culture through iron chelation. Overall, this observation describes two novel chemical scaffolds with antifungal activity against diverse fungal pathogens.

Advancements and challenges in antifungal therapeutic development.

Over recent decades, the global burden of fungal disease has expanded dramatically. It is estimated that fungal disease kills approximately 1.5 million individuals annually; however, the true worldwide burden of fungal infection is thought to be higher due to existing gaps in diagnostics and clinical understanding of mycotic disease. The development of resistance to antifungals across diverse pathogenic fungal genera is an increasingly common and devastating phenomenon due to the dearth of available antifungal classes. These factors necessitate a coordinated response by researchers, clinicians, public health agencies, and the pharmaceutical industry to develop new antifungal strategies, as the burden of fungal disease continues to grow. This review provides a comprehensive overview of the new antifungal therapeutics currently in clinical trials, highlighting their spectra of activity and progress toward clinical implementation. We also profile up-and-coming intracellular proteins and pathways primed for the development of novel antifungals targeting their activity. Ultimately, we aim to emphasize the importance of increased investment into antifungal therapeutics in the current continually evolving landscape of infectious disease.

Respiration supports intraphagosomal filamentation and escape of Candida albicans from macrophages.

IMPORTANCE: Candida albicans is a leading human fungal pathogen that often causes life-threatening infections in immunocompromised individuals. The ability of C. albicans to transition between yeast and filamentous forms is key to its virulence, and this occurs in response to many host-relevant cues, including engulfment by host macrophages. While previous efforts identified C. albicans genes required for filamentation in other conditions, the genes important for this morphological transition upon internalization by macrophages remained largely enigmatic. Here, we employed a functional genomic approach to identify genes that enable C. albicans filamentation within macrophages and uncovered a role for the mitochondrial ribosome, respiration, and the SNF1 AMP-activated kinase complex. Additionally, we showed that glucose uptake and glycolysis by macrophages support C. albicans filamentation. This work provides insights into the metabolic dueling that occurs during the interaction of C. albicans with macrophages and identifies vulnerabilities in C. albicans that could serve as promising therapeutic targets.

DYRK-family kinases regulate Candida albicans morphogenesis and virulence through the Ras1/PKA pathway.

IMPORTANCE: Candida albicans is an opportunistic human fungal pathogen that frequently causes life-threatening infections in immunocompromised individuals. To cause disease, the fungus employs several virulence traits, including its ability to transition between yeast and filamentous states. Previous work identified a role for the kinase Yak1 in regulating C. albicans filamentation. Here, we demonstrate that Yak1 regulates morphogenesis through the canonical cAMP/PKA pathway and that this regulation is environmentally contingent, as host-relevant concentrations of CO2 bypass the requirement of Yak1 for C. albicans morphogenesis. We show a related kinase, Pom1, is important for filamentation in the absence of Yak1 under these host-relevant conditions, as deletion of both genes blocked filamentous growth under all conditions tested. Finally, we demonstrate that Yak1 is required for filamentation in a mouse model of C. albicans dermatitis using genetic and pharmacological approaches. Overall, our results expand our understanding of how Yak1 regulates an important virulence trait in C. albicans.

Roles of Hsp90 in Candida albicans morphogenesis and virulence.

Hsp90 is a conserved molecular chaperone that facilitates the folding and function of hundreds of client proteins, many of which serve as core hubs of signal transduction networks. Hsp90 has a critical role in virulence of the opportunistic fungal pathogen Candida albicans, which exists as a natural commensal of the human microbiota and is a leading cause of invasive fungal infections, particularly in immunocompromised individuals. The ability of C. albicans to cause disease is tightly coupled to its capacity to undergo a morphogenetic transition between yeast and filamentous forms. Here, we describe the complex mechanisms by which Hsp90 regulates C. albicans morphogenesis and virulence, and explore the potential of targeting fungal Hsp90 as a therapeutic strategy to combat fungal infections.

Multifactor transcriptional control of alternative oxidase induction integrates diverse environmental inputs to enable fungal virulence.

Metabolic flexibility enables fungi to invade challenging host environments. In Candida albicans, a common cause of life-threatening infections in humans, an important contributor to flexibility is alternative oxidase (Aox) activity. Dramatic induction of this activity occurs under respiratory-stress conditions, which impair the classical electron transport chain (ETC). Here, we show that deletion of the inducible AOX2 gene cripples C. albicans virulence in mice by increasing immune recognition. To investigate further, we examined transcriptional regulation of AOX2 in molecular detail under host-relevant, ETC-inhibitory conditions. We found that multiple transcription factors, including Rtg1/Rtg3, Cwt1/Zcf11, and Zcf2, bind and regulate the AOX2 promoter, conferring thousand-fold levels of inducibility to AOX2 in response to distinct environmental stressors. Further dissection of this complex promoter revealed how integration of stimuli ranging from reactive species of oxygen, nitrogen, and sulfur to reduced copper availability is achieved at the transcriptional level to regulate AOX2 induction and enable pathogenesis.

Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity.

Rising drug resistance among pathogenic fungi, paired with a limited antifungal arsenal, poses an increasing threat to human health. To identify antifungal compounds, we screened the RIKEN natural product depository against representative isolates of four major human fungal pathogens. This screen identified NPD6433, a triazenyl indole with broad-spectrum activity against all screening strains, as well as the filamentous mold Aspergillus fumigatus. Mechanistic studies indicated that NPD6433 targets the enoyl reductase domain of fatty acid synthase 1 (Fas1), covalently inhibiting its flavin mononucleotide-dependent NADPH-oxidation activity and arresting essential fatty acid biosynthesis. Robust Fas1 inhibition kills Candida albicans, while sublethal inhibition impairs diverse virulence traits. At well-tolerated exposures, NPD6433 extended the lifespan of nematodes infected with azole-resistant C. albicans. Overall, identification of NPD6433 provides a tool with which to explore lipid homeostasis as a therapeutic target in pathogenic fungi and reveals a mechanism by which Fas1 function can be inhibited.

Competency Assessment of Pediatric Intensive Care Nurses.

One of the biggest challenges that clinical nurse educators at the unit level face today is measuring the ongoing competency of nursing staff members to ensure provision of high-quality, evidence-based care. Pediatric nursing leaders at an urban, level I trauma teaching institution in the southwestern United States used a shared governance approach to create a standardized competency assessment tool for pediatric intensive care unit nurses. Donna Wright's competency assessment model was used as a framework to guide the tool's development. The adoption of the standardized competency assessment tool was aligned with the organization's institutional goals and enabled clinical nurse educators to comprehensively evaluate staff members on a regular basis. This standardized competency assessment system for pediatric intensive care nurses is more effective than use of a practice-based, task-oriented assessment method and has improved nursing leaders' ability to staff the pediatric intensive care unit safely.

Construction of Candida albicans Strains with ATP-Analog-Sensitive Protein Kinase A and Hog1.

Candida albicans is an opportunistic human fungal pathogen and a member of the mucosal microbiota. To survive in the host and cause disease, C. albicans utilizes several virulence traits, including the ability to respond and adapt to diverse stressors, as well as the morphogenetic switch between yeast and filamentous morphologies. While complex cellular circuitry governs these virulence attributes, the following two kinase-mediated signaling pathways play particularly critical roles in controlling these processes: the Hog1 mitogen-activated protein kinase (MAPK) cascade and the protein kinase A (PKA) pathway. Here, we describe the construction of C. albicans strains harboring substitutions in the ATP-binding pockets of Hog1 and the catalytic subunits of PKA, Tpk1, and Tpk2 to render their activities sensitive to the addition of bulky ATP analogs. Specifically, inhibition by the ATP analog 1NM-PP1 resulted in phenotypes characteristic of the corresponding homozygous deletion mutants for each kinase gene. These strains represent a toolset for the rapid and specific inhibition of PKA and Hog1 kinase activity to further understand their roles in regulating C. albicans morphogenesis and stress responses. IMPORTANCE As an opportunistic pathogen in humans, the fungus Candida albicans relies on virulence traits to cause disease. They include the ability to transition from yeast to filamentous morphologies and the ability to grow in diverse environmental stress conditions, including nutrient limitation, as well as osmotic and heat shock. Previous work identified the following two kinases that play a critical role in regulating these responses: Hog1 and PKA. Here, we generated versions of each kinase that are sensitive to inhibition by a bulky ATP analog, 1NM-PP1. In the presence of the analog, kinase activity is inhibited rapidly and specifically, facilitating the analysis of both kinases in regulating C. albicans morphogenesis and stress responses. Together, these strains represent an important toolset to further our understanding of C. albicans biology and virulence.

Chemical-Genetic Approaches for Exploring Mode of Action of Antifungal Compounds in the Fungal Pathogen Candida albicans.

Candida albicans is a prevalent fungal pathogen of humans that can cause both superficial and life-threatening disease, primarily in immunocompromised populations. Currently, antifungal drug classes available to treat fungal infections remain limited and the emergence of drug-resistant strains threatens antifungal efficacy, necessitating the discovery and development of additional therapeutics. The construction of the C. albicans double-barcoded heterozygous deletion collection (DBC) enables the rapid and systematic assessment of haploinsufficiency phenotypes in a pooled format. Specifically, this functional genomics resource can be used to identify heterozygous deletion mutants that are hypersensitive to compounds in order to define putative cellular targets and/or other modifiers of compound activity. Here, we describe protocols to characterize the mode of action of small molecules using the C. albicans DBC, including how to prepare compound-treated cultures, isolate genomic DNA, amplify strain-specific barcodes, and prepare DNA libraries for high-throughput sequencing. This technique provides a powerful approach to elucidate the compound mechanism of action in order to bolster the antifungal pipeline.

Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments.

Candida albicans is a leading cause of mycotic infection. The ability to transition between yeast and filamentous forms is critical to C. albicans virulence and complex signaling pathways regulate this process. Here, we screened a C. albicans protein kinase mutant library in six environmental conditions to identify regulators of morphogenesis. We identified the uncharacterized gene orf19.3751 as a negative regulator of filamentation and follow-up investigations implicated a role for orf19.3751 in cell cycle regulation. We also uncovered a dual role for the kinases Ire1 and protein kinase A (Tpk1 and Tpk2) in C. albicans morphogenesis, specifically as negative regulators of wrinkly colony formation on solid medium but positive regulators of filamentation in liquid medium. Further analyses suggested Ire1 modulates morphogenesis in both media states in part through the transcription factor Hac1 and in part through independent mechanisms. Overall, this work provides insights into the signaling governing morphogenesis in C. albicans.

Ent2 Governs Morphogenesis and Virulence in Part through Regulation of the Cdc42 Signaling Cascade in the Fungal Pathogen Candida albicans.

The ability to transition between yeast and filamentous growth states is critical for virulence of the leading human fungal pathogen Candida albicans. Large-scale genetic screens have identified hundreds of genes required for this morphological switch, but the mechanisms by which many of these genes orchestrate this developmental transition remain largely elusive. In this study, we characterized the role of Ent2 in governing morphogenesis in C. albicans. We showed that Ent2 is required for filamentous growth under a wide range of inducing conditions and is also required for virulence in a mouse model of systemic candidiasis. We found that the epsin N-terminal homology (ENTH) domain of Ent2 enables morphogenesis and virulence and does so via a physical interaction with the Cdc42 GTPase-activating protein (GAP) Rga2 and regulation of its localization. Further analyses revealed that overexpression of the Cdc42 effector protein Cla4 can overcome the requirement for the ENTH-Rga2 physical interaction, indicating that Ent2 functions, at least in part, to enable proper activation of the Cdc42-Cla4 signaling pathway in the presence of a filament-inducing cue. Overall, this work characterizes the mechanism by which Ent2 regulates hyphal morphogenesis in C. albicans, unveils the importance of this factor in enabling virulence in an in vivo model of systemic candidiasis and adds to the growing understanding of the genetic control of a key virulence trait. IMPORTANCE Candida albicans is a leading human fungal pathogen that can cause life-threatening infections in immunocompromised individuals, with mortality rates of ~40%. The ability of this organism to grow in both yeast and filamentous forms is critical for the establishment of systemic infection. Genomic screens have identified many genes required for this morphological transition, yet our understanding of the mechanisms that regulate this key virulence trait remains incomplete. In this study, we characterized Ent2 as a core regulator of C. albicans morphogenesis. We show that Ent2 regulates hyphal morphogenesis through an interaction between its ENTH domain and the Cdc42 GAP, Rga2, which signals through the Cdc42-Cla4 signaling pathway. Finally, we show that the Ent2 protein, and specifically its ENTH domain, is required for virulence in a mouse model of systemic candidiasis. Overall, this work identifies Ent2 as a key regulator of filamentation and virulence in C. albicans.

Expanding pediatric services to include adults during the COVID-19 pandemic.

BACKGROUND: During COVID-19, pediatric hospital admissions decreased, leaving many inpatient pediatric units at reduced capacity. Pediatric units could be adapted for use as inpatient beds for adult patients. AIMS: The specific aims were to describe the rapid expansion of pediatric services to include adult patients and examine the characteristics of adult patients treated and managed by pediatric providers and nurses. METHODS: This quality improvement project used a plan-do-study-act cycle to evaluate project implementation and effectiveness with cycle changes. Adults age 19 to 30 were admitted to the pediatric unit. Process, outcome, and balancing measures were used as measurements. RESULTS: A total of 88 adult patients were admitted. No rapid responses were called during the intervention period. The number of adverse safety events were compared ten months prior to the ten months post intervention and was not statistically significant (p = 0.194). CONCLUSION: This project serves as a model for other pediatric medical-surgical units and PICUs to rapidly develop a plan to serve adult patients, whether amid the COVID-19 pandemic or adult patients with chronic childhood disorders. These results suggest that pediatric staff can safely care for adults when a pediatric team structure and familiar environment are maintained.

Bacterial-fungal interactions and their impact on microbial pathogenesis.

Microbial communities of the human microbiota exhibit diverse effects on human health and disease. Microbial homeostasis is important for normal physiological functions and changes to the microbiota are associated with many human diseases including diabetes, cancer, and colitis. In addition, there are many microorganisms that are either commensal or acquired from environmental reservoirs that can cause diverse pathologies. Importantly, the balance between health and disease is intricately connected to how members of the microbiota interact and affect one another's growth and pathogenicity. However, the mechanisms that govern these interactions are only beginning to be understood. In this review, we outline bacterial-fungal interactions in the human body, including examining the mechanisms by which bacteria govern fungal growth and virulence, as well as how fungi regulate bacterial pathogenesis. We summarize advances in the understanding of chemical, physical, and protein-based interactions, and their role in exacerbating or impeding human disease. We focus on the three fungal species responsible for the majority of systemic fungal infections in humans: Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. We conclude by summarizing recent studies that have mined microbes for novel antimicrobials and antivirulence factors, highlighting the potential of the human microbiota as a rich resource for small molecule discovery.

The Trisubstituted Isoxazole MMV688766 Exerts Broad-Spectrum Activity against Drug-Resistant Fungal Pathogens through Inhibition of Lipid Homeostasis.

Candida species are among the most prevalent causes of systemic fungal infection, posing a growing threat to public health. While Candida albicans is the most common etiological agent of systemic candidiasis, the frequency of infections caused by non-albicans Candida species is rising. Among these is Candida auris, which has emerged as a particular concern. Since its initial discovery in 2009, it has been identified worldwide and exhibits resistance to all three principal antifungal classes. Here, we endeavored to identify compounds with novel bioactivity against C. auris from the Medicines for Malaria Venture's Pathogen Box library. Of the five hits identified, the trisubstituted isoxazole MMV688766 emerged as the only compound displaying potent fungicidal activity against C. auris, as well as other evolutionarily divergent fungal pathogens. Chemogenomic profiling, as well as subsequent metabolomic and phenotypic analyses, revealed that MMV688766 disrupts cellular lipid homeostasis, driving a decrease in levels of early sphingolipid intermediates and fatty acids and a concomitant increase in lysophospholipids. Experimental evolution to further probe MMV688766's mode of action in the model fungus Saccharomyces cerevisiae revealed that loss of function of the transcriptional regulator HAL9 confers resistance to MMV688766, in part through the upregulation of the lipid-binding chaperone HSP12, a response that appears to assist in tolerating MMV688766-induced stress. The novel mode of action we have uncovered for MMV688766 against drug-resistant fungal pathogens highlights the broad utility of targeting lipid homeostasis to disrupt fungal growth and how screening structurally-diverse chemical libraries can provide new insights into resistance-conferring stress responses of fungi. IMPORTANCE As widespread antimicrobial resistance threatens to propel the world into a postantibiotic era, there is a pressing need to identify mechanistically distinct antimicrobial agents. This is of particular concern when considering the limited arsenal of drugs available to treat fungal infections, coupled with the emergence of highly drug-resistant fungal pathogens, including Candida auris. In this work, we demonstrate that existing libraries of drug-like chemical matter can be rich resources for antifungal molecular scaffolds. We discovered that the small molecule MMV688766, from the Pathogen Box library, displays previously undescribed broad-spectrum fungicidal activity through perturbation of lipid homeostasis. Characterization of the mode of action of MMV688766 provided new insight into the protective mechanisms fungi use to cope with the disruption of lipid homeostasis. Our findings highlight that elucidating the genetic circuitry required to survive in the presence of cellular stress offers powerful insights into the biological pathways that govern this important phenotype.

The GARP complex is required for filamentation in Candida albicans.

Candida albicans is an opportunistic fungal pathogen that causes superficial infections in immunocompetent individuals, as well as life-threatening systemic disease in immunocompromised patients. A key virulence trait of this pathogen is its ability to transition between yeast and filamentous morphologies. A functional genomic screen to identify novel regulators of filamentation previously revealed VPS53 as being important for morphogenesis. Vps53 belongs to the Golgi-associated retrograde protein (GARP) complex, which mediates retrograde trafficking from the endosome to the trans-Golgi network. Here, we explored the role of the entire GARP complex in regulating morphogenesis. Deletion of any of the four genes encoding GARP complex subunits severely impaired filamentation in response to diverse filament-inducing cues, including upon internalization by macrophages. Genetic pathway analysis revealed that while hyperactivation of protein kinase A (PKA) signaling is insufficient to drive filamentation in GARP complex mutants, these strains are capable of filamentation upon overexpression of transcriptional activators or upon deletion of transcriptional repressors of hyphal morphogenesis. Finally, compromise of the GARP complex induced lipotoxicity, and pharmacological inhibition of sphingolipid biosynthesis phenocopied genetic compromise of the GARP complex by impairing filamentation. Together, this work identifies the GARP complex as an important mediator of filamentation in response to multiple inducing cues, maps genetic circuitry important for filamentation upon compromise of GARP function, and supports a model whereby GARP deficiency impairs lipid homeostasis, which is important for supporting filamentous growth in C. albicans.

Antifungal discovery.

Fungi have a profound impact on human health, leading to billions of infections and millions of deaths worldwide each year. Exacerbating the public health burden is the continued emergence of drug-resistant fungal pathogens coupled with a dearth of treatment options to combat serious infections. Despite this health threat, scientific advances in chemistry, genetics, and biochemistry methodologies have enabled novel antifungal compounds to be discovered. Here, we describe current approaches for the discovery and characterization of novel antifungals, focusing on the identification of novel chemical matter and elucidation of the cellular target of bioactive compounds, followed by a review of the most promising emerging therapies in the antifungal-development pipeline.

Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility.

Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diverse diseases, yet kinases remain untapped in the quest for new antifungals. Here, we performed a comprehensive analysis of the C. albicans kinome to identify genes for which loss-of-function confers hypersensitivity to the two most widely deployed antifungals, echinocandins and azoles. Through this analysis, we found a role for the casein kinase 1 (CK1) homologue Hrr25 in regulating tolerance to both antifungals as well as target-mediated echinocandin resistance. Follow-up investigations established that Hrr25 regulates these responses through its interaction with the SBF transcription factor. Thus, we provide insights into the circuitry governing cellular responses to antifungals and implicate Hrr25 as a key mediator of drug resistance.