scholarly journals The inositol polyphosphate kinase Ipk1 transcriptionally regulates mitochondrial functions in Candida albicans

2020 ◽  
Vol 20 (6) ◽  
Author(s):  
Hangqi Zhu ◽  
Nali Zhu ◽  
Liping Peng ◽  
Bing Zhang ◽  
Qilin Yu ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mitochondrial Function ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Polyphosphate Kinase ◽  
Inositol Polyphosphate ◽  
Human Beings ◽  
Respiratory Chain Complexes ◽  
Cellular Processes ◽  
Mitochondrial Functions

ABSTRACT Inositol polyphosphates (IPs) is an important family of signaling molecules that regulate multiple cellular processes, such as chromatin remodeling, transcription and mRNA export. Inositol polyphosphate kinases, as the critical enzymes for production and transformation of IPs, directly determine the intracellular levels of IPs and therefore are involved in many cellular processes. However, its roles in Candida albicans, the leading fungal pathogen in human beings, remain to be investigated. In this study, we identified the inositol polyphosphate kinase Ipk1 in C. albicans and found that it localizes in the nucleus. Moreover, in the ipk1Δ/Δ mutant, the activity of mitochondrial respiratory chain complexes and the mitochondrial function was severely impaired, which were associated with down-regulation of mitochondrial function-related genes revealed by transcription profiling analysis. The ipk1Δ/Δ mutant also displayed hypersensitivity to a series of environmental stresses, such as antifungal drugs, oxidants, cell wall perturbing agents and macrophage attacks, followed by attenuation of virulence in a mouse systematic infection model. These findings firstly reported the importance of inositol polyphosphate kinase Ipk1 in C. albicans, especially its role in mitochondrial function maintenance and pathogenicity.

Role of the inositol polyphosphate kinase Vip1 in autophagy and pathogenesis in Candida albicans

2020 ◽  
Vol 15 (14) ◽  
pp. 1363-1377 ◽  
Author(s):  
Tianyu Ma ◽  
Qilin Yu ◽  
Congcong Ma ◽  
Xiaolong Mao ◽  
Yingzheng Liu ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Systemic Infection ◽  
Eukaryotic Cells ◽  
Polyphosphate Kinase ◽  
Acidic Ph ◽  
Inositol Polyphosphate ◽  
Cellular Processes ◽  
Increased Sensitivity ◽  
Vacuolar Ph

Aim: Inositol polyphosphate kinases are involved in regulation of many cellular processes in eukaryotic cells. In this study, we investigated the functions of the inositol polyphosphate kinase Vip1 in autophagy and pathogenicity of Candida albicans. Results: Loss of Vip1 caused significantly increased sensitivity to nitrogen source starvation, abnormal localization and degradation of autophagy protein, higher vacuolar pH and higher (rather than lower) intracellular ATP levels compared with control strains. Besides, the mutant showed attenuated hyphal development and virulence during systemic infection to mice. Conclusion: The results reveal that Vip1 is important to autophagy of C. albicans. The maintenance of vacuolar acidic pH contributed to the role of Vip1 in autophagy. Vip1 is also required for pathogenicity of C. albicans.

scholarly journals Increase of Virulence and Its Phenotypic Traits in Drug-Resistant Strains of Candida albicans

2008 ◽  
Vol 52 (3) ◽  
pp. 927-936 ◽  
Author(s):  
Letizia Angiolella ◽  
Anna Rita Stringaro ◽  
Flavia De Bernardis ◽  
Brunella Posteraro ◽  
Mariantonietta Bonito ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Biological Properties ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Phenotypic Traits ◽  
Homozygous Mutation ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT There is concern about the rise of antifungal drug resistance, but little is known about comparative biological properties and pathogenicity of drug-resistant strains. We generated fluconazole (FLC; CO23RFLC)- or micafungin (FK; CO23RFK)-resistant strains of Candida albicans by treating a FLC- and FK-susceptible strain of this fungus (CO23S) with stepwise-increasing concentrations of either drug. Molecular analyses showed that CO23RFLC had acquired markedly increased expression of the drug-resistance efflux pump encoded by the MDR1 gene, whereas CO23RFK had a homozygous mutation in the FSK1 gene. These genetic modifications did not alter to any extent the growth capacity of the drug-resistant strains in vitro, either at 28°C or at 37°C, but markedly increased their experimental pathogenicity in a systemic mouse infection model, as assessed by the overall mortality and target organ invasion. Interestingly, no apparent increase in the vaginopathic potential of the strains was observed with an estrogen-dependent rat vaginal infection. The increased pathogenicity of drug-resistant strains for systemic infection was associated with a number of biochemical and physiological changes, including (i) marked cellular alterations associated with a different expression and content of major cell wall polysaccharides, (ii) more rapid and extensive hypha formation in both liquid and solid media, and (iii) increased adherence to plastic and a propensity for biofilm formation. Overall, our data demonstrate that experimentally induced resistance to antifungal drugs, irrespective of drug family, can substantially divert C. albicans biology, affecting in particular biological properties of potential relevance for deep-seated candidiasis.

scholarly journals Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 72
Author(s):  
Laura Mena ◽  
Muriel Billamboz ◽  
Rogatien Charlet ◽  
Bérangère Desprès ◽  
Boualem Sendid ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Caenorhabditis Elegans ◽  
Inhibitory Effect ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Screening Methods ◽  
Antifungal Compounds ◽  
Chemical Library ◽  
Antifungal Properties ◽  
New Compounds

Candidiasis, caused by the opportunistic yeast Candida albicans, is the most common fungal infection today. Resistance of C. albicans to current antifungal drugs has emerged over the past decade leading to the need for novel antifungal agents. Our aim was to select new antifungal compounds by library-screening methods and to assess their antifungal effects against C. albicans. After screening 90 potential antifungal compounds from JUNIA, a chemical library, two compounds, 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-3,6-dimethylpyridin-2(1H)-one (PYR) and (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (TRI), were identified as having potential antifungal activity. Treatment with PYR and TRI resulted in a significant reduction of C. albicans bioluminescence as well as the number of fungal colonies, indicating rapid fungicidal activity. These two compounds were also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. PYR and TRI had an inhibitory effect on Candida biofilm formation and reduced the thickness of the mannan cell wall. In a Caenorhabditis elegans infection model, PYR and TRI decreased the mortality of nematodes infected with C. albicans and enhanced the expression of antimicrobial genes that promote C. albicans elimination. Overall, PYR and TRI showed antifungal properties against C. albicans by exerting fungicidal activities and enhancing the antimicrobial gene expression of Caenorhabditis elegans.

scholarly journals Mitochondrial Sorting and Assembly Machinery Subunit Sam37 in Candida albicans: Insight into the Roles of Mitochondria in Fitness, Cell Wall Integrity, and Virulence

2012 ◽  
Vol 11 (4) ◽  
pp. 532-544 ◽  
Author(s):  
Yue Qu ◽  
Branka Jelicic ◽  
Filomena Pettolino ◽  
Andrew Perry ◽  
Tricia L. Lo ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Mitochondrial Function ◽  
Drug Tolerance ◽  
Cell Wall Integrity ◽  
Mitochondrial Outer Membrane ◽  
Wall Structure ◽  
Content Type ◽  
Mitochondrial Functions ◽  
Insight Into

ABSTRACT Recent studies indicate that mitochondrial functions impinge on cell wall integrity, drug tolerance, and virulence of human fungal pathogens. However, the mechanistic aspects of these processes are poorly understood. We focused on the mitochondrial outer membrane SAM ( S orting and A ssembly M achinery) complex subunit Sam37 in Candida albicans . Inactivation of SAM37 in C. albicans leads to a large reduction in fitness, a phenotype not conserved with the model yeast Saccharomyces cerevisiae . Our data indicate that slow growth of the sam37ΔΔ mutant results from mitochondrial DNA loss, a new function for Sam37 in C. albicans , and from reduced activity of the essential SAM complex subunit Sam35. The sam37ΔΔ mutant was hypersensitive to drugs that target the cell wall and displayed altered cell wall structure, supporting a role for Sam37 in cell wall integrity in C. albicans . The sensitivity of the mutant to membrane-targeting antifungals was not significantly altered. The sam37ΔΔ mutant was avirulent in the mouse model, and bioinformatics showed that the fungal Sam37 proteins are distant from their animal counterparts and could thus represent potential drug targets. Our study provides the first direct evidence for a link between mitochondrial function and cell wall integrity in C. albicans and is further relevant for understanding mitochondrial function in fitness, antifungal drug tolerance, and virulence of this major pathogen. Beyond the relevance to fungal pathogenesis, this work also provides new insight into the mitochondrial and cellular roles of the SAM complex in fungi.

scholarly journals The Zinc Finger Protein Mig1 Regulates Mitochondrial Function and Azole Drug Susceptibility in the Pathogenic Fungus Cryptococcus neoformans

mSphere ◽  
2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Mélissa Caza ◽  
Guanggan Hu ◽  
Michael Price ◽  
John R. Perfect ◽  
James W. Kronstad
Keyword(s):  
Cryptococcus Neoformans ◽  
Mitochondrial Function ◽  
Drug Susceptibility ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Oxygen Species ◽  
Content Type ◽  
New Targets ◽  
Expression Of Genes ◽  
Mitochondrial Functions

ABSTRACT Fungal pathogens of humans are difficult to treat, and there is a pressing need to identify new targets for antifungal drugs and to obtain a detailed understanding of fungal proliferation in vertebrate hosts. In this study, we examined the roles of the regulatory proteins Mig1 and HapX in mitochondrial function and antifungal drug susceptibility in the fungus Cryptococcus neoformans. This pathogen is a particular threat to the large population of individuals infected with human immunodeficiency virus (HIV). Our analysis revealed regulatory interactions between Mig1 and HapX, and a role for Mig1 in mitochondrial functions, including respiration, tolerance for reactive oxygen species, and expression of genes for iron consumption and iron acquisition functions. Importantly, loss of Mig1 increased susceptibility to the antifungal drug fluconazole, which is commonly used to treat cryptococcal disease. These studies highlight an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs. The opportunistic pathogen Cryptococcus neoformans causes fungal meningoencephalitis in immunocompromised individuals. In previous studies, we found that the Hap complex in this pathogen represses genes encoding mitochondrial respiratory functions and tricarboxylic acid (TCA) cycle components under low-iron conditions. The orthologous Hap2/3/4/5 complex in Saccharomyces cerevisiae exerts a regulatory influence on mitochondrial functions, and Hap4 is subject to glucose repression via the carbon catabolite repressor Mig1. In this study, we explored the regulatory link between a candidate ortholog of the Mig1 protein and the HapX component of the Hap complex in C. neoformans. This analysis revealed repression of MIG1 by HapX and activation of HAPX by Mig1 under low-iron conditions and Mig1 regulation of mitochondrial functions, including respiration, tolerance for reactive oxygen species, and expression of genes for iron consumption and iron acquisition functions. Consistently with these regulatory functions, a mig1Δ mutant had impaired growth on inhibitors of mitochondrial respiration and inducers of ROS. Furthermore, deletion of MIG1 provoked a dysregulation in nutrient sensing via the TOR pathway and impacted the pathway for cell wall remodeling. Importantly, loss of Mig1 increased susceptibility to fluconazole, thus further establishing a link between azole antifungal drugs and mitochondrial function. Mig1 and HapX were also required together for survival in macrophages, but Mig1 alone had a minimal impact on virulence in mice. Overall, these studies provide novel insights into a HapX/Mig1 regulatory network and reinforce an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs. IMPORTANCE Fungal pathogens of humans are difficult to treat, and there is a pressing need to identify new targets for antifungal drugs and to obtain a detailed understanding of fungal proliferation in vertebrate hosts. In this study, we examined the roles of the regulatory proteins Mig1 and HapX in mitochondrial function and antifungal drug susceptibility in the fungus Cryptococcus neoformans. This pathogen is a particular threat to the large population of individuals infected with human immunodeficiency virus (HIV). Our analysis revealed regulatory interactions between Mig1 and HapX, and a role for Mig1 in mitochondrial functions, including respiration, tolerance for reactive oxygen species, and expression of genes for iron consumption and iron acquisition functions. Importantly, loss of Mig1 increased susceptibility to the antifungal drug fluconazole, which is commonly used to treat cryptococcal disease. These studies highlight an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs.

scholarly journals Identification of genome-wide alternative splicing events in sequential, isogenic clinical isolates of Candida albicans reveals a mechanism important for drug resistance and tolerance to cellular stress

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Suraya Muzafar ◽  
Neeraj Chauhan ◽  
Ravi Datta Sharma ◽  
Rajendra Prasad
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Alternative Splicing ◽  
Differential Expression ◽  
Single Gene ◽  
Antifungal Drugs ◽  
Protein Isoforms ◽  
Gene Splicing ◽  
Cellular Processes ◽  
Genome Wide

Alternative gene splicing (AS) is a process by which a single gene can give rise to different protein isoforms, generating proteome diversity. Despite recent advances in our understanding of AS in basic cellular processes, the role of AS in drug resistance and fungal pathogenesis is poorly understood. In Candida albicans, approximately 6% of the genes contain introns. Considering this low and random distribution of introns, we focused our study on alternative splicing (AS) and its impact on the development of drug resistance, an area largely unexplored in this yeast. We performed comparative RNA sequencing of sequential isogenic azole sensitive and resistant isolates of C. albicans. The analysis revealed differential expression of splice junctions/isoforms in 14 genes, between the drug sensitive and resistant isolates. Furthermore, C. albicans WT cells exposed to antifungal drugs, heat stress or metal deficiency also showed differential expression of isoforms for the genes undergoing AS. In this study we present data on the effect of AS on the function of SOD3. The C. albicans SOD3 has a single intron and is important for the removal of superoxide radicals. The overexpression of the two isoforms of SOD3 in its null background highlighted importance of spliced isoform in complementing the susceptibility to menadione. However, the two isoforms did not differ in rescuing the susceptibility of sod3Δ/Δto Amphotericin B. Collectively, these data suggest that AS may be a novel mechanism in C. albicans for stress adaptation and overcoming drug resistance.

scholarly journals The Contribution of Candida albicans Vacuolar ATPase Subunit V1B, Encoded byVMA2, to Stress Response, Autophagy, and Virulence Is Independent of Environmental pH

2014 ◽  
Vol 13 (9) ◽  
pp. 1207-1221 ◽  
Author(s):  
Hallie S. Rane ◽  
Stella M. Bernardo ◽  
Summer R. Hayek ◽  
Jessica L. Binder ◽  
Karlett J. Parra ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Specific Activity ◽  
Carbon Sources ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Atpase Subunit ◽  
Content Type ◽  
Degradative Enzymes ◽  
And Function

ABSTRACTCandida albicansvacuoles are central to many critical biological processes, including filamentation andin vivovirulence. The V-ATPase proton pump is a multisubunit complex responsible for organellar acidification and is essential for vacuolar biogenesis and function. To study the function of the V1B subunit ofC. albicansV-ATPase, we constructed a tetracycline-regulatableVMA2mutant, tetR-VMA2. Inhibition ofVMA2expression resulted in the inability to grow at alkaline pH and altered resistance to calcium, cold temperature, antifungal drugs, and growth on nonfermentable carbon sources. Furthermore, V-ATPase was unable to fully assemble at the vacuolar membrane and was impaired in proton transport and ATPase-specific activity.VMA2repression led to vacuolar alkalinization in addition to abnormal vacuolar morphology and biogenesis. Key virulence-related traits, including filamentation and secretion of degradative enzymes, were markedly inhibited. These results are consistent with previous studies ofC. albicansV-ATPase; however, differential contributions of the V-ATPase Voand V1subunits to filamentation and secretion are observed. We also make the novel observation that inhibition ofC. albicansV-ATPase results in increased susceptibility to osmotic stress. Notably, V-ATPase inhibition under conditions of nitrogen starvation results in defects in autophagy. Lastly, we show the first evidence that V-ATPase contributes to virulence in an acidicin vivosystem by demonstrating that the tetR-VMA2mutant is avirulent in aCaenorhabditis elegansinfection model. This study illustrates the fundamental requirement of V-ATPase for numerous key virulence-related traits inC. albicansand demonstrates that the contribution of V-ATPase to virulence is independent of host pH.

scholarly journals The Novel J-Domain Protein Mrj1 Is Required for Mitochondrial Respiration and Virulence in Cryptococcus neoformans

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Linda C. Horianopoulos ◽  
Guanggan Hu ◽  
Mélissa Caza ◽  
Kerstin Schmitt ◽  
Peter Overby ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Antifungal Drugs ◽  
Complex Iii ◽  
Content Type ◽  
Mitochondrial Functions ◽  
J Domain ◽  
Domain Protein

ABSTRACT The opportunistic fungal pathogen Cryptococcus neoformans must adapt to the mammalian environment to establish an infection. Proteins facilitating adaptation to novel environments, such as chaperones, may be required for virulence. In this study, we identified a novel mitochondrial co-chaperone, Mrj1 (mitochondrial respiration J-domain protein 1), necessary for virulence in C. neoformans. The mrj1Δ and J-domain-inactivated mutants had general growth defects at both routine laboratory and human body temperatures and were deficient in the major virulence factor of capsule elaboration. The latter phenotype was associated with cell wall changes and increased capsular polysaccharide shedding. Accordingly, the mrj1Δ mutant was avirulent in a murine model of cryptococcosis. Mrj1 has a mitochondrial localization and co-immunoprecipitated with Qcr2, a core component of complex III of the electron transport chain. The mrj1 mutants were deficient in mitochondrial functions, including growth on alternative carbon sources, growth without iron, and mitochondrial polarization. They were also insensitive to complex III inhibitors and hypersensitive to an alternative oxidase (AOX) inhibitor, suggesting that Mrj1 functions in respiration. In support of this conclusion, mrj1 mutants also had elevated basal oxygen consumption rates which were completely abolished by the addition of the AOX inhibitor, confirming that Mrj1 is required for mitochondrial respiration through complexes III and IV. Furthermore, inhibition of complex III phenocopied the capsule and cell wall defects of the mrj1 mutants. Taken together, these results indicate that Mrj1 is required for normal mitochondrial respiration, a key aspect of adaptation to the host environment and virulence. IMPORTANCE Cryptococcus neoformans is the causative agent of cryptococcal meningitis, a disease responsible for ∼15% of all HIV-related deaths. Unfortunately, development of antifungal drugs is challenging because potential targets are conserved between humans and C. neoformans. In this context, we characterized a unique J-domain protein, Mrj1, which lacks orthologs in humans. We showed that Mrj1 was required for normal mitochondrial respiration and that mutants lacking Mrj1 were deficient in growth, capsule elaboration, and virulence. Furthermore, we were able to phenocopy the defects in growth and capsule elaboration by inhibiting respiration. This result suggests that the role of Mrj1 in mitochondrial function was responsible for the observed virulence defects and reinforces the importance of mitochondria to fungal pathogenesis. Mitochondria are difficult to target, as their function is also key to human cells; however, Mrj1 presents an opportunity to target a unique fungal protein required for mitochondrial function and virulence in C. neoformans.

scholarly journals Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species

2019 ◽  
Author(s):  
Hassan E. Eldesouky ◽  
Ehab A. Salama ◽  
Xiaoyan Li ◽  
Tony R. Hazbun ◽  
Abdelrahman S. Mayhoub ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Candida Albicans ◽  
Drug Therapy ◽  
Structural Investigation ◽  
Nile Red ◽  
Multidrug Resistant ◽  
Human Medicine ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Synergistic Relationship

AbstractThe limited number of systemic antifungals and the emergence of azole-resistant Candida species constitute a growing challenge to human medicine. Combinatorial drug therapy represents an appealing approach to enhance the activity of, or restore the susceptibility to current antifungals. Here, we evaluated the fluconazole chemosensitization activity of the Pharmakon 1600 drug library against azole-resistant Candida albicans. We identified 33 non-antifungal drugs that were able to restore susceptibility to fluconazole in an azole-resistant C. albicans. Structural investigation of identified hits revealed phenylpentanol scaffold as a valuable pharmacophore for re-sensitizing azole-resistant Candida species to the effect of current azole antifungal drugs. All phenylpentanol derivatives displayed potent fluconazole chemosensitizing activities (ΣFICI 0.13-0.28) and were able to reduce fluconazole’s MIC by 15-31 fold against the tested strain. Particularly pitavastatin displayed the most potent fluconazole chemosensitizing activity (ΣFICI 0.06-0.50). The pitavastatin-fluconazole combination displayed a broad-spectrum synergistic relationship against 90% of the tested strains, including strains of C. albicans, C. glabrata, and C. auris. Moreover, pitavastatin restored the susceptibility of the multidrug-resistant C. auris to the antifungal activities of itraconazole and voriconazole. Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model. Both pitavastatin and the plain phenylpentanol scaffold were able to interfere significantly with Candida’s efflux activities as demonstrated by Nile Red efflux assays and flow cytometry. This study presents phenylpentanol derivatives as potent azole chemosensitizers that warrant further investigation.

scholarly journals Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

2014 ◽  
Vol 58 (7) ◽  
pp. 3697-3707 ◽  
Author(s):  
Anscha Mari Troskie ◽  
Marina Rautenbach ◽  
Nicolas Delattin ◽  
Johan Arnold Vosloo ◽  
Margitta Dathe ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Membrane Integrity ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Synergistic Activity ◽  
Significant Activity ◽  
Content Type ◽  
Micromolar Range

ABSTRACTTyrocidines are cationic cyclodecapeptides fromBacillus aneurinolyticusthat are characterized by potent antibacterial and antimalarial activities. In this study, we show that various tyrocidines have significant activity against planktonicCandida albicansin the low-micromolar range. These tyrocidines also preventedC. albicansbiofilm formationin vitro. Studies with the membrane-impermeable dye propidium iodide showed that the tyrocidines disrupt the membrane integrity of matureC. albicansbiofilm cells. This membrane activity correlated with the permeabilization and rapid lysis of model fungal membranes containing phosphatidylcholine and ergosterol (70:30 ratio) induced by the tyrocidines. The tyrocidines exhibited pronounced synergistic biofilm-eradicating activity in combination with two key antifungal drugs, amphotericin B and caspofungin. Using aCaenorhabditis elegansinfection model, we found that tyrocidine A potentiated the activity of caspofungin. Therefore, tyrocidines are promising candidates for further research as antifungal drugs and as agents for combinatorial treatment.

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