A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets

Zamith-Miranda, Daniel; Heyman, Heino M.; Burnet, Meagan C.; Couvillion, Sneha P.; Zheng, Xueyun; Munoz, Nathalie; Nelson, William C.; Kyle, Jennifer E.; Zink, Erika M.; Weitz, Karl K.; Bloodsworth, Kent J.; Clair, Geremy; Zucker, Jeremy D.; Teuton, Jeremy R.; Payne, Samuel H.; Kim, Young-Mo; Reyes Gil, Morayma; Baker, Erin S.; Bredeweg, Erin L.; Nosanchuk, Joshua D.; Nakayasu, Ernesto S.; Kronstad, ed., James W.

doi:10.1128/mBio.02972-21

Title: A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets

Journal Article · Tue Dec 21 00:00:00 EST 2021 · mBio (Online)

DOI:https://doi.org/10.1128/mBio.02972-21· OSTI ID:1832247

^[1]; Heyman, Heino M. ^[2]; Burnet, Meagan C. ^[2]; Couvillion, Sneha P. ^[2]; Zheng, Xueyun ^[2]; Munoz, Nathalie ^[3];

^[2]; Kyle, Jennifer E. ^[2]; Zink, Erika M. ^[2]; Weitz, Karl K. ^[2]; Bloodsworth, Kent J. ^[2];

^[2];

^[2]; Teuton, Jeremy R. ^[2];

^[4];

^[2]; Reyes Gil, Morayma ^[5]; Baker, Erin S. ^[6]; Bredeweg, Erin L. ^[3]; Nosanchuk, Joshua D. ^[1] more »

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA, Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
Environmental and Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, USA
Department of Biology, Brigham Young University, Provo, Utah, USA
Hematology Laboratory, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
Department of Chemistry, North Carolina State University, Raleigh, North Carolina, USA

Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid metabolism is key for developing new drugs and a better understanding of fungal pathogenesis. Here, we built a comprehensive map of the Histoplasma capsulatum lipid metabolic pathway by incorporating proteomic and lipidomic analyses. We performed genetic complementation and overexpression of H. capsulatum genes in Saccharomyces cerevisiae to validate reactions identified in the map and to determine enzymes responsible for catalyzing orphan reactions. The map led to the identification of both the fatty acid desaturation and the sphingolipid biosynthesis pathways as targets for drug development. We found that the sphingolipid biosynthesis inhibitor myriocin, the fatty acid desaturase inhibitor thiocarlide, and the fatty acid analog 10-thiastearic acid inhibit H. capsulatum growth in nanomolar to low-micromolar concentrations. These compounds also reduced the intracellular infection in an alveolar macrophage cell line. Overall, this lipid metabolic map revealed pathways that can be targeted for drug development.

View Journal Article

Cite

Export

Save

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC05-76RL01830; R21 AI124797; P42 ES027704

OSTI ID:: 1832247

Alternate ID(s):: OSTI ID: 1836231

Report Number(s):: PNNL-SA-152496; e02972-21

Journal Information:: mBio (Online), Journal Name: mBio (Online) Vol. 12 Journal Issue: 6; ISSN 2150-7511

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

References (63)

LIQUID: an-open source software for identifying lipids in LC-MS/MS-based lipidomics data Kyle, Jennifer E.; Crowell, Kevin L.; Casey, Cameron P. Bioinformatics, Vol. 33, Issue 11 https://doi.org/10.1093/bioinformatics/btx046	journal	January 2017
Epidemiology of Histoplasmosis Outbreaks, United States, 1938–2013 Benedict, Kaitlin; Mody, Rajal K. Emerging Infectious Diseases, Vol. 22, Issue 3 https://doi.org/10.3201/eid2203.151117	journal	March 2016
LPT1 Encodes a Membrane-bound O-Acyltransferase Involved in the Acylation of Lysophospholipids in the Yeast Saccharomyces cerevisiae Tamaki, Hisanori; Shimada, Atsushi; Ito, Yoshihiro Journal of Biological Chemistry, Vol. 282, Issue 47 https://doi.org/10.1074/jbc.M704509200	journal	November 2007
Antifungal therapeutics for dimorphic fungal pathogens Goughenour, Kristie D.; Rappleye, Chad A. Virulence, Vol. 8, Issue 2 https://doi.org/10.1080/21505594.2016.1235653	journal	September 2016
Lipid profiles of conidia of Aspergillus niger and a fatty acid auxotroph Chattopadhyay, Panchanon; Banerjee, Santu Kumar; Sen, Kalyani Canadian Journal of Microbiology, Vol. 33, Issue 12 https://doi.org/10.1139/m87-195	journal	December 1987
Functional Characterization of Flax Fatty Acid Desaturase FAD2 and FAD3 Isoforms Expressed in Yeast Reveals a Broad Diversity in Activity Radovanovic, Natasa; Thambugala, Dinushika; Duguid, Scott Molecular Biotechnology, Vol. 56, Issue 7 https://doi.org/10.1007/s12033-014-9737-1	journal	February 2014
Amphotericin forms an extramembranous and fungicidal sterol sponge Anderson, Thomas M.; Clay, Mary C.; Cioffi, Alexander G. Nature Chemical Biology, Vol. 10, Issue 5 https://doi.org/10.1038/nchembio.1496	journal	March 2014
Antimycobacterial Activities of Isoxyl and New Derivatives through the Inhibition of Mycolic Acid Synthesis Phetsuksiri, Benjawan; Baulard, Alain R.; Cooper, Andrea M. Antimicrobial Agents and Chemotherapy, Vol. 43, Issue 5 https://doi.org/10.1128/AAC.43.5.1042	journal	May 1999
Chemical evaluation of fatty acid desaturases as drug targets in Trypanosoma cruzi Alloatti, Andrés; Testero, Sebastián A.; Uttaro, Antonio D. International Journal for Parasitology, Vol. 39, Issue 9 https://doi.org/10.1016/j.ijpara.2009.01.011	journal	July 2009
Myriocin Significantly Increases the Mortality of a Non-Mammalian Model Host during Candida Pathogenesis Melo, Nadja Rodrigues de; Abdrahman, Ahmed; Greig, Carolyn PLoS ONE, Vol. 8, Issue 11 https://doi.org/10.1371/journal.pone.0078905	journal	November 2013
Lipid profiles of Aspergillus niger and its unsaturated fatty acid auxotroph, UFA ₂ Chattopadhyay, Panchanon; Banerjee, Santu Kumar; Sen, Kalyani Canadian Journal of Microbiology, Vol. 31, Issue 4 https://doi.org/10.1139/m85-067	journal	April 1985
Amphotericin primarily kills yeast by simply binding ergosterol Gray, K. C.; Palacios, D. S.; Dailey, I. Proceedings of the National Academy of Sciences, Vol. 109, Issue 7 https://doi.org/10.1073/pnas.1117280109	journal	January 2012
Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa Mediators of Inflammation, Vol. 2017 https://doi.org/10.1155/2017/9870679	journal	January 2017
Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities Palacios, D. S.; Dailey, I.; Siebert, D. M. Proceedings of the National Academy of Sciences, Vol. 108, Issue 17 https://doi.org/10.1073/pnas.1015023108	journal	February 2011
MPLEx: a Robust and Universal Protocol for Single-Sample Integrative Proteomic, Metabolomic, and Lipidomic Analyses Nakayasu, Ernesto S.; Nicora, Carrie D.; Sims, Amy C. mSystems, Vol. 1, Issue 3 https://doi.org/10.1128/mSystems.00043-16	journal	May 2016
Vesicular transport in Histoplasma capsulatum : an effective mechanism for trans-cell wall transfer of proteins and lipids in ascomycetes Albuquerque, Priscila Costa; Nakayasu, Ernesto S.; Rodrigues, Marcio L. Cellular Microbiology, Vol. 10, Issue 8 https://doi.org/10.1111/j.1462-5822.2008.01160.x	journal	August 2008
Antifungal Activity of Acylhydrazone Derivatives against Sporothrix spp. Artunduaga Bonilla, Jhon Jhamilton; Honorato, Leandro; Haranahalli, Krupanandan Antimicrobial Agents and Chemotherapy, Vol. 65, Issue 5 https://doi.org/10.1128/AAC.02593-20	journal	April 2021
The quantitative proteome of a human cell line Beck, Martin; Schmidt, Alexander; Malmstroem, Johan Molecular Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1038/msb.2011.82	journal	January 2011
MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data Pluskal, Tomáš; Castillo, Sandra; Villar-Briones, Alejandro BMC Bioinformatics, Vol. 11, Issue 1 https://doi.org/10.1186/1471-2105-11-395	journal	July 2010
Lipidomic Analysis of Extracellular Vesicles from the Pathogenic Phase of Paracoccidioides brasiliensis Vallejo, Milene C.; Nakayasu, Ernesto S.; Longo, Larissa V. G. PLoS ONE, Vol. 7, Issue 6 https://doi.org/10.1371/journal.pone.0039463	journal	June 2012
Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite Strader, Cherilyn R.; Pearce, Cedric J.; Oberlies, Nicholas H. Journal of Natural Products, Vol. 74, Issue 4 https://doi.org/10.1021/np2000528	journal	April 2011
Antibody Binding Alters the Characteristics and Contents of Extracellular Vesicles Released by Histoplasma capsulatum Matos Baltazar, Ludmila; Nakayasu, Ernesto S.; Sobreira, Tiago J. P. mSphere, Vol. 1, Issue 2 https://doi.org/10.1128/mSphere.00085-15	journal	March 2016
The readily extracted lipids of Histoplasma capsulatum and Blastomyces dermatitidis Domer, Judith E.; Hamilton, James G. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, Vol. 231, Issue 3 https://doi.org/10.1016/0005-2760(71)90114-7	journal	May 1971
Identification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput Drug-Repurposing Screen Cheng, Yu-Shan; Roma, Jose Santinni; Shen, Min Antimicrobial Agents and Chemotherapy, Vol. 65, Issue 4 https://doi.org/10.1128/AAC.01305-20	journal	March 2021
Inhibition of ceramide de novo synthesis by myriocin produces the double effect of reducing pathological inflammation and exerting antifungal activity against A. fumigatus airways infection Caretti, Anna; Torelli, Riccardo; Perdoni, Federica Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1860, Issue 6 https://doi.org/10.1016/j.bbagen.2016.02.014	journal	June 2016
Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans Rittershaus, P. C. Journal of Clinical Investigation, Vol. 116, Issue 6 https://doi.org/10.1172/JCI27890	journal	June 2006
The Role of Ceramide Synthases in the Pathogenicity of Cryptococcus neoformans Munshi, Mansa A.; Gardin, Justin M.; Singh, Ashutosh Cell Reports, Vol. 22, Issue 6 https://doi.org/10.1016/j.celrep.2018.01.035	journal	February 2018
Multistate Epidemiology of Histoplasmosis, United States, 2011–2014 ¹ Armstrong, Paige A.; Jackson, Brendan R.; Haselow, Dirk Emerging Infectious Diseases, Vol. 24, Issue 3 https://doi.org/10.3201/eid2403.171258	journal	March 2017
Deciphering the Pathways of Death of Histoplasma capsulatum -Infected Macrophages: Implications for the Immunopathogenesis of Early Infection Deepe, George S.; Buesing, William R. The Journal of Immunology, Vol. 188, Issue 1 https://doi.org/10.4049/jimmunol.1102175	journal	November 2011
Unique Mechanism of Action of the Thiourea Drug Isoxyl on Mycobacterium tuberculosis Phetsuksiri, Benjawan; Jackson, Mary; Scherman, Hataichanok Journal of Biological Chemistry, Vol. 278, Issue 52 https://doi.org/10.1074/jbc.M311209200	journal	December 2003
Studies on the transformation of intact yeast cells by the LiAc/SS-DNA/PEG procedure Gietz, R. Daniel; Schiestl, Robert H.; Willems, Andrew R. Yeast, Vol. 11, Issue 4, p. 355-360 https://doi.org/10.1002/yea.320110408	journal	April 1995
Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids Mor, Visesato; Rella, Antonella; Farnoud, Amir M. mBio, Vol. 6, Issue 3 https://doi.org/10.1128/mBio.00647-15	journal	July 2015
Phylogenetic Distribution of Fungal Sterols Weete, John D.; Abril, Maritza; Blackwell, Meredith PLoS ONE, Vol. 5, Issue 5 https://doi.org/10.1371/journal.pone.0010899	journal	May 2010
Antifungal activity of Myriocin on clinically relevant Aspergillus fumigatus strains producing biofilm Perdoni, Federica; Signorelli, Paola; Cirasola, Daniela BMC Microbiology, Vol. 15, Issue 1 https://doi.org/10.1186/s12866-015-0588-0	journal	October 2015
Principles of cellular resource allocation revealed by condition-dependent proteome profiling Metzl-Raz, Eyal; Kafri, Moshe; Yaakov, Gilad eLife, Vol. 6 https://doi.org/10.7554/eLife.28034	journal	August 2017
Sterols and Fatty Acids of the Mortierellaceae: Taxonomic Implications Weete, J. D.; Gandhi, S. R. Mycologia, Vol. 91, Issue 4 https://doi.org/10.2307/3761250	journal	July 1999
Pharmacology and Safety of Tetradecylthioacetic Acid (TTA): Phase-1 Study Pettersen, Reidar J.; Salem, Mohamed; Skorve, Jon Journal of Cardiovascular Pharmacology, Vol. 51, Issue 4 https://doi.org/10.1097/FJC.0b013e3181673be0	journal	January 2008
Screening of Chemical Libraries for New Antifungal Drugs against Aspergillus fumigatus Reveals Sphingolipids Are Involved in the Mechanism of Action of Miltefosine dos Reis, Thaila Fernanda; Horta, Maria Augusta Crivelente; Colabardini, Ana Cristina mBio, Vol. 12, Issue 4 https://doi.org/10.1128/mBio.01458-21	journal	August 2021
Hospitalizations for Endemic Mycoses: A Population-Based National Study Chu, J. H.; Feudtner, C.; Heydon, K. Clinical Infectious Diseases, Vol. 42, Issue 6 https://doi.org/10.1086/500405	journal	March 2006
Isoxyl particles for pulmonary delivery: In vitro cytotoxicity and potency Wang, Chenchen; Hickey, Anthony J. International Journal of Pharmaceutics, Vol. 396, Issue 1-2 https://doi.org/10.1016/j.ijpharm.2010.06.037	journal	August 2010
Salmonella modulates metabolism during growth under conditions that induce expression of virulence genes Kim, Young-Mo; Schmidt, Brian J.; Kidwai, Afshan S. Molecular BioSystems, Vol. 9, Issue 6 https://doi.org/10.1039/c3mb25598k	journal	January 2013
Multi-omics Signature of Candida auris , an Emerging and Multidrug-Resistant Pathogen Zamith-Miranda, Daniel; Heyman, Heino M.; Cleare, Levi G. mSystems, Vol. 4, Issue 4 https://doi.org/10.1128/mSystems.00257-19	journal	June 2019
FiehnLib: Mass Spectral and Retention Index Libraries for Metabolomics Based on Quadrupole and Time-of-Flight Gas Chromatography/Mass Spectrometry Kind, Tobias; Wohlgemuth, Gert; Lee, Do Yup Analytical Chemistry, Vol. 81, Issue 24 https://doi.org/10.1021/ac9019522	journal	December 2009
New Horizons in Antifungal Therapy Pianalto, Kaila; Alspaugh, J. Journal of Fungi, Vol. 2, Issue 4 https://doi.org/10.3390/jof2040026	journal	October 2016
Myriocin, a new Antifungal Antibiotic from Myriococcum Albomyces Kluepfel, Dieter; Bagli, Jehan; Baker, Harold The Journal of Antibiotics, Vol. 25, Issue 2 https://doi.org/10.7164/antibiotics.25.109	journal	January 1972
Cross‐species discovery of syncretic drug combinations that potentiate the antifungal fluconazole Spitzer, Michaela; Griffiths, Emma; Blakely, Kim M. Molecular Systems Biology, Vol. 7, Issue 1 https://doi.org/10.1038/msb.2011.31	journal	January 2011
Quantitative Analysis of Proteome and Lipidome Dynamics Reveals Functional Regulation of Global Lipid Metabolism Casanovas, Albert; Sprenger, Richard R.; Tarasov, Kirill Chemistry & Biology, Vol. 22, Issue 3 https://doi.org/10.1016/j.chembiol.2015.02.007	journal	March 2015
Sterol composition of the vine powdery mildew fungus, Uncinula necator: Comparison of triadimenol-sensitive and resistant strains Debieu, D. Phytochemistry, Vol. 39, Issue 2 https://doi.org/10.1016/0031-9422(95)00015-Y	journal	May 1995
Mass-spectrometry-based draft of the human proteome Wilhelm, Mathias; Schlegl, Judith; Hahne, Hannes Nature, Vol. 509, Issue 7502 https://doi.org/10.1038/nature13319	journal	May 2014
Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids Lazzarini, Cristina; Haranahalli, Krupanandan; Rieger, Robert Antimicrobial Agents and Chemotherapy, Vol. 62, Issue 5 https://doi.org/10.1128/AAC.00156-18	journal	May 2018
Global and Multi-National Prevalence of Fungal Diseases—Estimate Precision Bongomin, Felix; Gago, Sara; Oladele, Rita Journal of Fungi, Vol. 3, Issue 4 https://doi.org/10.3390/jof3040057	journal	October 2017
Histoplasma capsulatum: More Widespread than Previously Thought Antinori, Spinello The American Journal of Tropical Medicine and Hygiene, Vol. 90, Issue 6 https://doi.org/10.4269/ajtmh.14-0175	journal	June 2014
Sterol distribution in arbuscular mycorrhizal fungi Grandmougin-Ferjani, Anne; Dalpé, Yolande; Hartmann, Marie-Andrée Phytochemistry, Vol. 50, Issue 6 https://doi.org/10.1016/S0031-9422(98)00636-0	journal	March 1999
Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies Burnet, Meagan C.; Zamith-Miranda, Daniel; Heyman, Heino M. Vaccines, Vol. 8, Issue 2 https://doi.org/10.3390/vaccines8020269	journal	June 2020
Concentration-dependent protein loading of extracellular vesicles released by Histoplasma capsulatum after antibody treatment and its modulatory action upon macrophages Baltazar, Ludmila Matos; Zamith-Miranda, Daniel; Burnet, Meagan C. Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-25665-5	journal	May 2018
Trypanosoma Cruzi Oleate Desaturase: Molecular Characterization and Comparative Analysis in Other Trypanosomatids Maldonado, Rosa A.; Kuniyoshi, Renata K.; Linss, Jutta G. Journal of Parasitology, Vol. 92, Issue 5 https://doi.org/10.1645/GE-845R.1	journal	October 2006
Candida albicans gains azole resistance by altering sphingolipid composition Gao, Jiaxin; Wang, Haitao; Li, Zeyao Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06944-1	journal	October 2018
MetaboliteDetector: Comprehensive Analysis Tool for Targeted and Nontargeted GC/MS Based Metabolome Analysis Hiller, Karsten; Hangebrauk, Jasper; Jäger, Christian Analytical Chemistry, Vol. 81, Issue 9 https://doi.org/10.1021/ac802689c	journal	May 2009
Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung Dautel, Sydney E.; Kyle, Jennifer E.; Clair, Geremy Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep40555	journal	February 2017
Identification of bifunctional 12/ 3 fatty acid desaturases for improving the ratio of 3 to 6 fatty acids in microbes and plants Damude, H. G.; Zhang, H.; Farrall, L. Proceedings of the National Academy of Sciences, Vol. 103, Issue 25 https://doi.org/10.1073/pnas.0511079103	journal	June 2006
Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance Ghannoum, Mahmoud A.; Rice, Louis B. Clinical Microbiology Reviews, Vol. 12, Issue 4 https://doi.org/10.1128/CMR.12.4.501	journal	October 1999
Media matters! Alterations in the loading and release of Histoplasma capsulatum extracellular vesicles in response to different nutritional milieus Cleare, Levi G.; Zamith, Daniel; Heyman, Heino M. Cellular Microbiology, Vol. 22, Issue 9 https://doi.org/10.1111/cmi.13217	journal	June 2020
Antifungal effect of voriconazole on intracellular Candida glabrata, Candida krusei and Candida parapsilosis in human monocyte-derived macrophages Bopp, Lawrence H.; Baltch, Aldona L.; Ritz, William J. Journal of Medical Microbiology, Vol. 55, Issue 7 https://doi.org/10.1099/jmm.0.46393-0	journal	July 2006

Similar Records

Remodeling of the Histoplasma Capsulatum Membrane Induced by Monoclonal Antibodies

Journal Article · Tue Jun 02 00:00:00 EDT 2020 · Vaccines · OSTI ID:1832247

Burnet, Meagan C.; Zamith-Miranda, Daniel; Heyman, Heino M.; +4 more

Antibody Binding Alters the Characteristics and Contents of Extracellular Vesicles Released by Histoplasma capsulatum

Journal Article · Wed Mar 30 00:00:00 EDT 2016 · mSphere · OSTI ID:1832247

Matos Baltazar, Ludmila; Nakayasu, Ernesto S.; Sobreira, Tiago J. P.; +5 more

Concentration-dependent protein loading of extracellular vesicles released by Histoplasma capsulatum after antibody treatment and its modulatory action upon macrophages

Journal Article · Wed May 23 00:00:00 EDT 2018 · Scientific Reports · OSTI ID:1832247

Baltazar, Ludmila Matos; Zamith-Miranda, Daniel; Burnet, Meagan C.; +4 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Histoplasma capsulatum
lipid metabolism
drug target
platelet-activating factor
multi-omics analysis

Title: A Histoplasma capsulatum Lipid Metabolic Map Identifies Antifungal Targets

Citation Formats

References (63)

Similar Records

Related Subjects