The identification of new pathways and compounds that can enhance caspofungin activity against Aspergillus fumigatus

• Grant number: 21/04977-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: July 01, 2022
• End date: June 30, 2027
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Gustavo Henrique Goldman
• Grantee: Gustavo Henrique Goldman
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Iran Malavazi
• Associated researchers: Taicia Pacheco Fill
• Associated research grant(s): 24/18720-4 - NMR spectroscopic approaches to study cell wall organization and antifungal drug resistance in fungi, AP.R SPRINT
• Associated scholarship(s): 24/17349-0 - Theoretical/practical learning in microbiological laboratory techniques., BP.TT; 23/00206-0 - Characterization of mitogenomes of Aspergillus fumigatus populations with strains resistant and susceptible to antifungal drugs, BP.PD; 22/13603-4 - Large-scale data integration to study gene expression dynamics of Aspergillus fumigatus metabolic pathways related to caspofungin's antifungal action, BP.TT; + associated scholarships 22/08556-7 - Identification of new pathways and compounds that enhance Caspofungin and Voriconazole activity against Aspergillus fumigatus, BP.PD; 22/08642-0 - Characterization of transcriptional programs important for resistance and tolerance to Caspofungin, BP.PD; 17/07536-4 - Molecular Mechanisms Involved in Paradoxal Growth Induced by Caspofungin in Aspergillus fumigatus, BP.PD - associated scholarships

Abstract

Invasive Pulmonary Aspergillosis (IPA), mainly caused by Aspergillus fumigatus, is a major infectious complication with mortality rates as high as 90% depending on the immunological status of the host. Azoles are fungicidal drugs for A. fumigatus and the main antifungal agents recommended for IPA. Echinocandins, such as caspofungin (CSP), represent a second line therapy and target the fungal cell wall by inhibiting 1,3-beta-D-glucan synthase, which is responsible for the assembly of beta-D-glucan, a major component of the fungal cell wall. CSP is fungistatic against A. fumigatus and treatment with CSP leads to hyphae with defects in growth and morphology. One of the objectives of our project is to investigate how the signal transduction for the fungal response to CSP is mediated via oxylipins. The fungal oxylipin 5,8-dihydroxyoctadecadienoic acid (5S,8R-diHODE) is important for cellular differentiation and lateral branching in A. fumigatus. CSP induces A. fumigatus hyperbranching and phenocopies the increased lateral branching observed when this fungus is exposed to 5S,8R-diHODE. Preliminary results from our laboratory indicate that the null mutant for ppoA gene that encodes the fatty acid oxygenase 5,8-linoleate diol synthase (5,8-LDS) responsible for the formation of 5S,8R-diHODE is resistant to CSP while the strain overexpressing ppoA is more sensitive to CSP than the corresponding wild-type strain. We also observed that the null mutant for ppoC (ppoC encodes a fatty acid dehydrogenase) has lost the Caspofungin Paradoxical Effect (CPE). We propose to identify through a combination of RNAseq, metabolomics and molecular genetics which genes are modulated by 5S,8R-LDs, 8R-HODE, and CSP. We will identify these genes by comparing the corresponding wild-type strain with the null mutants of ppoA and ppoC, and also by using representative strains from a collection of about 70 worldwide A. fumigatus clinical isolates with different degrees of CSP sensitivity and tolerance. As a second objective, we will also evaluate A. fumigatus wild-type and null ppoA mutant growth alone or synergistically with CSP and libraries of compounds and chemical probes that could synergize and potentiate CSP. Finally, as a third objective, we will investigate a collection of 11 transcription factors previously implicated in caspofungin resistance and CPE and will determine if they are modulated by oxylipins. This can open new avenues for the identification of new metabolic pathways involved in caspofungin resistance and tolerance and can provide the development of novel CSP-based antifungal therapy. (AU)

Scientific publications

(19)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZHAO, SHU; MARTIN-VICENTE, ADELA; COLABARDINI, ANA CRISTINA; SILVA, LILIAN PEREIRA; RINKER, DAVID C.; FORTWENDEL, JARROD R.; GOLDMAN, GUSTAVO HENRIQUE; GIBBONS, JOHN G.. Genomic and Molecular Identification of Genes Contributing to the Caspofungin Paradoxical Effect in Aspergillus fumigatus. MICROBIOLOGY SPECTRUM, v. N/A, p. 18-pg., 2022-09-12. (21/04977-5, 16/21392-2, 17/07536-4)

ALVES DE CASTRO, PATRICIA; FIGUEIREDO PINZAN, CAMILA; DOS REIS, THAILA FERNANDA; VALERO, CLARA; VAN RHIJN, NORMAN; MENEGATTI, CARLA; DE FREITAS MIGLIORINI, IVAN LUCAS; BROMLEY, MICHAEL; FLEMING, ALASTAIR B.; TRAYNOR, AIMEE M.; et al. Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection. NATURE COMMUNICATIONS, v. 15, n. 1, p. 18-pg., 2024-01-02. (16/07870-9, 21/04977-5)

PINZAN, CAMILA FIGUEIREDO; VALERO, CLARA; DE CASTRO, PATRICIA ALVES; DA SILVA, JEFFERSON LUIZ; EARLE, KAYLEIGH; LIU, HONG; HORTA, MARIA AUGUSTA CRIVELENTE; KNIEMEYER, OLAF; KRUGER, THOMAS; PSCHIBUL, ANNICA; et al. Aspergillus fumigatus conidial surface-associated proteome reveals factors for fungal evasion and host immunity modulation. NATURE MICROBIOLOGY, v. 9, n. 10, p. 30-pg., 2024-08-27. (22/13603-4, 22/08796-8, 20/04923-0, 18/18257-1, 18/15549-1, 21/04977-5)

WASSANO, NATALIA S.; DA SILVA, GABRIELA B.; REIS, ARTUR H.; GERHARDT, JAQUELINE A.; ANTONIEL, EVERTON P.; AKIYAMA, DANIEL; REZENDE, CAROLINE P.; NEVES, LEANDRO X.; VASCONCELOS, ELTON J. R.; DE FIGUEIREDO, FERNANDA L.; et al. Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus. COMMUNICATIONS BIOLOGY, v. 7, n. 1, p. 17-pg., 2024-06-08. (18/09948-0, 20/06151-4, 22/03075-0, 21/04977-5, 22/02992-0, 22/05731-2)

DELBAJE, ENDREWS; DE CASTRO, PATRICIA ALVES; CALISE, DANTE G.; MENGYAO, NIU; HORTA, MARIA AUGUSTA CRIVELENTE; AKIYAMA, DANIEL YURI; PONTES, JOAO GUILHERME; FILL, TAICIA; KNIEMEYER, OLAF; KRUGER, THOMAS; et al. The Influence of Aspergillus fumigatus Fatty Acid Oxygenases PpoA and PpoC on Caspofungin Susceptibility. JOURNAL OF FUNGI, v. 10, n. 11, p. 23-pg., 2024-11-01. (23/00206-0, 22/02992-0, 21/04977-5)

CALISE, DANTE G.; PARK, SUNG CHUL; BOK, JIN WOO; GOLDMAN, GUSTAVO H.; KELLER, NANCY P.. An oxylipin signal confers protection against antifungal echinocandins in pathogenic aspergilli. NATURE COMMUNICATIONS, v. 15, n. 1, p. 15-pg., 2024-05-04. (21/04977-5)

DOS REIS, THAILA FERNANDA; DELBAJE, ENDREWS; PINZAN, CAMILA FIGUEIREDO; BASTOS, RAFAEL; ACKLOO, SUZANNE; FALLAH, SARA; LAFLAMME, BRADLEY; ROBBINS, NICOLE; COWEN, LEAH E.; GOLDMAN, GUSTAVO H.. The GPCR antagonist PPTN synergizes with caspofungin providing increased fungicidal activity against Aspergillus fumigatus. MICROBIOLOGY SPECTRUM, v. N/A, p. 22-pg., 2025-03-17. (21/04977-5, 23/00206-0)

DIEHL, CAMILA; PINZAN, CAMILA FIGUEIREDO; DE CASTRO, PATRICIA ALVES; DELBAJE, ENDREWS; CARNERO, LAURA C. GARCIA; SANCHEZ-LEON, EDDY; BHALLA, KABIR; KRONSTAD, JAMES W.; KIM, DONG-GYU; DOERING, TAMARA L.; et al. Brilacidin, a novel antifungal agent against Cryptococcus neoformans. MBIO, v. 15, n. 7, p. 28-pg., 2024-06-25. (22/13603-4, 22/08796-8, 21/10599-3, 21/04977-5)

MEAD, MATTHEW E.; DE CASTRO, PATRICIA ALVES L.; STEENWYK, JACOB L.; GANGNEUX, JEAN-PIERRE; HOENIGL, MARTIN; PRATTES, JUERGEN; RAUTEMAA-RICHARDSON, RIINA; GUEGAN, HELENE B.; MOORE, CAROLINE B.; LASS-FLOERL, CORNELIA; et al. COVID-19-Associated Pulmonary Aspergillosis Isolates Are Genomically Diverse but Similar to Each Other in Their Responses to Infection-Relevant Stresses. MICROBIOLOGY SPECTRUM, v. 11, n. 2, p. 11-pg., 2023-03-22. (21/04977-5, 20/01131-5)

SCOTT, JENNIFER; VALERO, CLARA; MATO-LOPEZ, ALVARO; DONALDSON, IAN J.; ROLDAN, ALEJANDRA; CHOWN, HARRY; VAN RHIJN, NORMAN; LOBO-VEGA, REBECA; GAGO, SARA; FURUKAWA, TAKANORI; et al. Aspergillus fumigatus Can Display Persistence to the Fungicidal Drug Voriconazole. MICROBIOLOGY SPECTRUM, v. 11, n. 2, p. 29-pg., 2023-03-13. (21/04977-5, 16/07870-9, 20/01131-5)

DOS REIS, THAILA FERNANDA; DIEHL, CAMILA; PINZAN, CAMILA FIGUEIREDO; DE CASTRO, PATRICIA ALVES; GOLDMAN, GUSTAVO H.. Brilacidin, a host defense peptide mimetic, potentiates ibrexafungerp antifungal activity against the human pathogenic fungus Aspergillus fumigatus. MICROBIOLOGY SPECTRUM, v. 12, n. 8, p. 7-pg., 2024-07-09. (21/04977-5)

DOS REIS, THAILA FERNANDA; DE CASTRO, PATRICIA ALVES; BASTOS, RAFAEL WESLEY; PINZAN, CAMILA FIGUEIREDO; SOUZA, PEDRO F. N.; ACKLOO, SUZANNE; HOSSAIN, MOHAMMAD ANWAR; DREWRY, DAVID HAROLD; ALKHAZRAJI, SONDUS; IBRAHIM, ASHRAF S.; et al. A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi. NATURE COMMUNICATIONS, v. 14, n. 1, p. 19-pg., 2023-04-12. (21/04977-5, 16/07870-9)

STEENWYK, JACOB L.; KNOWLES, SONJA; BASTOS, RAFAEL W.; BALAMURUGAN, CHARU; RINKER, DAVID; MEAD, MATTHEW E.; ROBERTS, CHRISTOPHER D.; RAJA, HUZEFA A.; LI, YUANNING; COLABARDINI, ANA CRISTINA; et al. Evolutionary origin and population diversity of a cryptic hybrid pathogen. NATURE COMMUNICATIONS, v. 15, n. 1, p. 16-pg., 2024-09-28. (16/07870-9, 21/04977-5, 22/16198-3, 22/12553-3)

CARNERO, LAURA C. GARCIA; PINZAN, CAMILA FIGUEIREDO; DIEHL, CAMILA; DE CASTRO, PATRICIA ALVES; PONTES, LAIS; RODRIGUES, ANDERSON MESSIAS; DOS REIS, THAILA F.; GOLDMAN, GUSTAVO H.. Milteforan, a promising veterinary commercial product against feline sporotrichosis. MICROBIOLOGY SPECTRUM, v. 12, n. 10, p. 18-pg., 2024-08-28. (22/08796-8, 22/09882-5, 21/04977-5, 22/08556-7)

RINKER, DAVID C.; SAUTERS, THOMAS J. C.; STEFFEN, KARIN; GUMILANG, ADIYANTARA; RAJA, HUZEFA A.; RANGEL-GRIMALDO, MANUEL; PINZAN, CAMILA FIGUEIREDO; DE CASTRO, PATRICIA ALVES; DOS REIS, THAILA FERNANDA; DELBAJE, ENDREWS; et al. Strain heterogeneity in a non-pathogenic Aspergillus fungus highlights factors associated with virulence. COMMUNICATIONS BIOLOGY, v. 7, n. 1, p. 16-pg., 2024-09-04. (23/00206-0, 21/04977-5)

VAN RHIJN, NORMAN; ZHAO, CAN; AL-FURAJI, NARJES; STORER, ISABELLE S. R.; VALERO, CLARA; GAGO, SARA; CHOWN, HARRY; BALDIN, CLARA; GRANT, RACHAEL-FORTUNE; BIN SHURAYM, HAJER; et al. Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging. NATURE COMMUNICATIONS, v. 15, n. 1, p. 16-pg., 2024-06-11. (21/04977-5, 20/01131-5, 18/00715-3)

DE CASTRO, PATRICIA ALVES; AKIYAMA, DANIEL YURI; PINZAN, CAMILA FIGUEIREDO; DOS REIS, THAILA FERNANDA; DELBAJE, ENDREWS; ROCHA, PETER; IZIDORO, MARIO AUGUSTO; SCHENKMAN, SERGIO; SUGIMOTO, SHINYA; TAKESHITA, NORIO; et al. Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa. MBIO, v. 16, n. 4, p. 31-pg., 2025-03-17. (21/12515-1, 21/04977-5, 21/07038-0, 24/11166-1)

SILVA, TATIANE C.; MOREIRA, SILVINO I.; DE SOUZA, DANIEL M.; CHRISTIANO JR, FELIX S.; GASPAROTO, MARIA C. G.; FRAAIJE, BART A.; GOLDMAN, GUSTAVO H.; CERESINI, PAULO C.. Resistance to Site-Specific Succinate Dehydrogenase Inhibitor Fungicides Is Pervasive in Populations of Black and Yellow Sigatoka Pathogens in Banana Plantations from Southeastern Brazil. AGRONOMY-BASEL, v. 14, n. 4, p. 22-pg., 2024-04-01. (18/21197-0, 17/50456-1, 20/07611-9, 19/12509-1, 21/04977-5, 21/03402-9)

FABRI, JOAO HENRIQUE TADINI MARILHANO; ROCHA, MARINA CAMPOS; FERNANDES, CAROLINE MOTA; CAMPANELLA, JONATAS ERICK MAIMONI; DA CUNHA, ANDERSON FERREIRA; DEL POETA, MAURIZIO; MALAVAZI, IRAN. The Heat Shock Transcription Factor HsfA Plays a Role in Membrane Lipids Biosynthesis Connecting Thermotolerance and Unsaturated Fatty Acid Metabolism in Aspergillus fumigatus. MICROBIOLOGY SPECTRUM, v. 11, n. 3, p. 24-pg., 2023-05-17. (21/04977-5, 19/00967-5, 21/11784-9)