Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria

• Grant number: 21/04464-8
• Support Opportunities: Regular Research Grants
• Duration: December 01, 2021 - May 31, 2024
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: André Gustavo Tempone Cardoso
• Grantee: André Gustavo Tempone Cardoso
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Alvaro Esteves Migotto ; Carlos Henrique Camargo ; Cledir Rodrigues Santos ; João Henrique Ghilardi Lago ; Luis Octávio Regasini ; Patricia Sartorelli
• Associated scholarship(s): 23/00428-2 - Microbial Compounds as Drug Candidates for Chagas Disease, BP.TT; 22/06180-0 - Microbial Compounds as Drug Candidates for Chagas disease, BP.TT

Abstract

Considering the advancement of the COVID-19 pandemic, the World Health Organization (WHO) has warned of its strong impact on vulnerable populations affected by neglected parasitic diseases and coinfections with SARS-CoV-2. The WHO also warned that due to the increase in hospital admissions, it became evident the need to expand the chemotherapy arsenal to fight multiresistant bacteria. Considering the therapeutic limitations in neglected protozooses, the significant increase in multidrug-resistant bacteria (ESKAPE), as well as the private sector's disregard for investing in new antibiotics, there is an urgent need for research into new drugs. Comprising a vast chemiodiversity, microbial and plant metabolites are one of the main sources of approved anti-infectious pharmaceutical prototypes. This project aims to identify new drug prototypes against Trypanosoma cruzi and Leishmania infantum, as well as for multiresistant "ESKAPE" bacteria, including Neisseria gonorrhoeae. Through the current project SPRINT FAPESP (2018 / 266557-7) with the University of Southampton (United Kingdom), partnerships with national universities (UFABC, USP, UNESP, UNIFESP), and international universities (University of Oxford -United Kingdom and Universität Münster -Germany), we will carry out an interdisciplinary project, using a well-established platform by the group, aiming at the study and selection of secondary metabolites of marine bacterial origin and compounds isolated from plants. Bacteria isolated from invertebrates and marine sediments will be identified by MALDI-TOF / MS and / or genetic sequencing. Using the OSMAC (One Strain Many Compounds) approach for the activation of cryptic genes, the differential production of secondary bacterial metabolites will be evaluated for antiparasitic / antimicrobial potential. Microbial active compounds, as well as plants, will be isolated through biomonitored studies using different separation and chromatographic techniques, supported by studies on nuclear magnetic resonance and LC-MS / MS (GNPS platform). The structural elucidation of active compounds will be carried out by spectrometric and spectroscopic techniques. Structural analogs based on natural bioactive compounds will be synthesized at Oxford, aiming at structure-activity studies. The compounds will be evaluated for potency (MIC / IC50) in microorganisms and toxicity in mammalian cells. Through in silico platforms, analyzes of the "drug-like" properties will be carried out, also eliminating interference compounds (PAINS). Studies of the antimicrobial and antiparasitic mechanisms of action will be carried out to evaluate changes in membranes, as well as bioenergetics and metabolic. Through an interdisciplinary and multicenter project, we intend to make available new prototypes for the synthesis of new therapeutic candidates, enabling pharmaceutical innovations for neglected parasitic diseases and multiresistant bacteria. (AU)

Scientific publications

(18)

(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)

VARELA, MARINA T.; AMARAL, MAIARA; ROMANELLI, MAIARA M.; LEVATTI, ERICA V. DE CASTRO; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Optimization of physicochemical properties is a strategy to improve drug-likeness associated with activity: Novel active and selective compounds against Trypanosoma cruzi. European Journal of Pharmaceutical Sciences, v. 171, p. 12-pg., 2022-04-01. (21/04464-8, 19/14167-0, 18/03918-2, 20/03637-3, 19/24028-8)

TEMPONE, ANDRE GUSTAVO; DOS SANTOS THEODORO, REINALDO; ROMANELLI, MAIARA MARIA; FERREIRA, DAYANA AGNES SANTOS; AMARAL, MAIARA; DE ASSIS, LETICIA RIBEIRO; CRUZ, LUCAS MONTEIRO SANTA; COSTA, ALAN ROBERTO; ZANELLA, ROSEMEIRE COBO; CHRISTODOULIDES, MYRON; et al. A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis. Chemico-Biological Interactions, v. 365, p. 8-pg., 2022-08-10. (14/18330-0, 21/04464-8, 18/26655-7, 19/11979-4, 17/50333-7, 18/15083-2, 09/53989-4)

ROMANELLI, MAIARA M.; AMARAL, MAIARA; THEVENARD, FERNANDA; CRUZ, LUCAS M. SANTA; REGASINI, LUIS O.; MIGOTTO, ALVARO E.; LAGO, JOAO HENRIQUE G.; TEMPONE, ANDRE G.. Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2 '-de-N-Methylaplysinopsin. ACS OMEGA, v. 7, n. 32, p. 10-pg., 2022-08-04. (17/50333-7, 21/04464-8, 21/02789-7)

CONSERVA, GEANNE A.; COSTA-SILVA, THAIS A.; QUIROS-GUERRERO, LUIS M.; MARCOURT, LAURENCE; WOLFENDER, JEAN-LUC; QUEIROZ, EMERSON F.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Kaempferol-3-O-alpha-(3,4-di-E-p-coumaroyl)-rhamnopyranoside from Nectandra oppositifolia releases Ca2+from intracellular pools of Trypanosoma cruzi affecting the bioenergetics system. Chemico-Biological Interactions, v. 349, NOV 1 2021. (16/20633-6, 21/04464-8, 21/02789-7, 18/18975-1)

DA COSTA-SILVA, THAIS A.; SILVA, MATHEUS L.; ANTAR, GUILHERME M.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Ent-kaurane diterpenes isolated from n-hexane extract of Baccharis sphenophylla by bioactivity-guided fractionation target the acidocalcisomes in Trypanosoma cruzi. Phytomedicine, v. 93, DEC 2021. (21/04464-8, 21/02789-7)

SILVA MAIOLINI, TATIANE CRISTINA; ROSA, WELTON; MIRANDA, DANIEL OLIVEIRA; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; PIRES BUENO, PAULA CAROLINA; DIAS, DANIELLE FERREIRA; CHAGAS DE PAULA, DANIELA APARECIDA; SARTORELLI, PATRICIA; LAGO, JOAO HENRIQUE G.; et al. Essential Oils from Different Myrtaceae Species from Brazilian Atlantic Forest Biome - Chemical Dereplication and Evaluation of Antitrypanosomal Activity. CHEMISTRY & BIODIVERSITY, v. 19, n. 6, p. 13-pg., 2022-05-30. (21/02789-7, 21/04464-8)

LIMA, MARTA LOPES; ABENGOZAR, MARIA A.; TORRES-SANTOS, EDUARDO CAIO; BORBOREMA, SAMANTA ETEL TREIGER; GODZIEN, JOANNA; LOPEZ-GONZALVEZD, ANGELES; BARBAS, CORAL; RIVAS, LUIS; TEMPONE, ANDRE GUSTAVO. Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis. BIOORGANIC CHEMISTRY, v. 127, p. 11-pg., 2022-07-13. (17/50333-7, 19/10434-4, 21/04464-8)

VARELA, MARINA T.; ROMANELLI, MAIARA; AMARAL, MAIARA; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity. SAUDI PHARMACEUTICAL JOURNAL, v. 31, n. 7, p. 9-pg., 2023-06-01. (21/04464-8, 19/24028-8, 19/14167-0, 18/03918-2)

AMARAL, MAIARA; VARELA, MARINA T.; KANT, RAVI; CHRISTODOULIDES, MYRON; FERNANDES, JOAO PAULO S.; TEMPONE, ANDRE G.. Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi. LIFE-BASEL, v. 13, n. 3, p. 17-pg., 2023-03-01. (21/04464-8, 18/26655-7, 17/50333-7, 18/03918-2, 19/24028-8, 18/25128-3)

ARAUJO, SHEILA C.; SOUSA, FERNANDA S.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.; HONORIO, KATHIA M.. Discovery of New Hits as Antitrypanosomal Agents by In Silico and In Vitro Assays Using Neolignan-Inspired Natural Products from Nectandra leucantha. Molecules, v. 26, n. 14, JUL 2021. (18/07885-1, 21/04464-8, 16/24524-7, 21/02789-7)

GALHARDO, THALITA S.; UENO, ANDERSON K.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; CARVALHO, WAGNER A.; FISCHMEISTER, CEDRIC; BRUNEAU, CHRISTIAN; MANDELLI, DALMO; LAGO, JOAO HENRIQUE G.. New derivatives from dehydrodieugenol B and its methyl ether displayed high anti-Trypanosoma cruzi activity and cause depolarization of the plasma membrane and collapse the mitochondrial membrane potential. Chemico-Biological Interactions, v. 366, p. 6-pg., 2022-09-07. (18/01258-5, 18/10279-6, 21/02789-7, 21/04464-8, 17/17044-1, 16/05006-5, 18/07885-1)

AMARAL, MAIARA; ASIKI, HANNAH; SEAR, CLAIRE E.; SINGH, SNIGDHA; PIEPER, PAULINE; HAUGLAND, MARIUS M.; ANDERSON, EDWARD A.; TEMPONE, ANDRE G.. Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis. RSC MEDICINAL CHEMISTRY, v. 14, n. 7, p. 7-pg., 2023-05-26. (18/25128-3, 21/04464-8, 17/50333-7)

DOS SANTOS, AUGUSTO L.; AMARAL, MAIARA; HASEGAWA, FLAVIA RIE; LAGO, JOAO HENRIQUE G.; TEMPONE, ANDRE G.; SARTORELLI, PATRICIA. (-)-T-Cadinol-a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)-Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi. FRONTIERS IN PHARMACOLOGY, v. 12, NOV 3 2021. (21/04464-8)

GALHARDO, THALITA S.; UENO, ANDERSON K.; CARVALHO, WAGNER A.; COSTA-SILVA, THAIS A.; GONCALVES, MARINA M.; ABIUZI, MARIANA B.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.; MANDELLI, DALMO; FISCHMEISTER, CEDRIC; et al. Synthesis of New Dehydrodieugenol Derivatives via Olefin Cross Metathesis and In Vitro Evaluation of Their Trypanocidal Activity. CATALYSTS, v. 13, n. 7, p. 13-pg., 2023-07-01. (21/12342-0, 21/04464-8, 18/10279-6, 17/50333-7, 21/02789-7, 18/01258-5, 18/07885-1)

FREIRE, VITOR F.; GUBIANI, JULIANA R.; SPENCER, TARA M.; HAJDU, EDUARDO; FERREIRA, ANTONIO G.; FERREIRA, DAYANA A. S.; DE CASTRO LEVATTI, ERICA, V; BURDETTE, JOANNA E.; CAMARGO, CARLOS HENRIQUE; TEMPONE, ANDRE G.; et al. Feature-Based Molecular Networking Discovery of Bromopyrrole Alkaloids from the Marine Sponge Agelas dispar. Journal of Natural Products, v. 85, n. 5, p. 11-pg., 2022-05-27. (19/17721-9, 17/06014-4, 20/03637-3, 13/50228-8, 21/04464-8)

THEVENARD, FERNANDA; BRITO, IVANILDO A.; COSTA-SILVA, THAIS A.; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. Enyne acetogenins from Porcelia macrocarpa displayed anti-Trypanosoma cruzi activity and cause a reduction in the intracellular calcium level. SCIENTIFIC REPORTS, v. 13, n. 1, p. 10-pg., 2023-06-24. (21/02789-7, 21/04464-8, 20/01221-4)

LEVATTI, ERICA V. DE CASTRO; COSTA-SILVA, THAIS A.; MORAIS, THIAGO R.; FERNANDES, JOAO PAULO S.; LAGO, JOAO HENRIQUE G.; TEMPONE, ANDRE G.. Lethal action of Licarin A derivatives in Leishmania (L.) infantum Imbalance of calcium and bioenergetic metabolism. Biochimie, v. 208, p. 10-pg., 2023-05-22. (21/02789-7, 21/04464-8, 17/50333-7)

SOUZA, DALETE CHRISTINE S.; COSTA-SILVA, THAIS A.; MORAIS, THIAGO R.; BRITO, JULIANA R.; FERREIRA, EDGARD A.; ANTAR, GUILHERME M.; SARTORELLI, PATRICIA; TEMPONE, ANDRE G.; LAGO, JOAO HENRIQUE G.. implified Derivatives of Dibenzylbutyrolactone Lignans from Hydrocotyle bonariensis as Antitrypanosomal Candidate. CHEMISTRY & BIODIVERSITY, v. 18, n. 10, SEP 2021. (19/13906-4, 21/02789-7, 21/04464-8)