Fighting bacterial resistance: metal complexes and the metallo-beta-lactamases inhibition

• Grant number: 17/12719-0
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2017 - August 31, 2019
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Camilla Abbehausen
• Grantee: Camilla Abbehausen
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated grant(s): 18/21120-8 - Selective targeting of zinc finger domains with metallodrugs for therapy of parasitic diseases, AP.R SPRINT

Abstract

The microbial resistance is a challenge that deserves the high attention of the scientific community. Among the bacterial resistance mechanisms, the most concerning is the emergence of novel types of hydrolytic enzymes, responsible for the inactivation of the beta-lactam antibiotics, the beta-lactamases, in special metallo-beta-lactamases. Our research group demonstrated that phosphinegold(I) complexes inhibit the activity of an enzymatic pool, composed by a serine-beta-lactamase and a metallo-beta-lactamase produced by Bacillus cereus. The data also suggested a selective inhibition of metallo-beta-lactamase. By rational drug development, several properties of these complexes can be improved to obtain a more effective and selective inhibitor. In this project, we propose the study of new phosphine and carbene N-heterocyclic ligands to develop novel metal complexes as inhibitors candidates. Several lateral groups of these ligands would be designed to attack specific sites of this enzymes, verified previously by our research group by in silico evaluations.In addition, dinuclear luminescent Au(I)-N-heterocyclic carbenes would be evaluated as probes in the study of inhibitory mechanisms of of the gold complexes by fluorescence spectroscopy. Also the cellular absorption will be monitotred by fluorescence microscopy. Moreover, we developed zinc complexes as model of metalo-beta-lactamases (mimetics). The models demonstrated that the coordination sphere of zinc influence the efficiency of hydrolysis. In this project we propose to evaluate the interaction of the complexes with substrate and inhibitors by X-ray absorption spectroscopy using synchrotron light. In order to improve the models, we propose the development of complexes using peptide conjugation, to mimic the active site microenvironment.Lastly, we propose to study inhibitors and mimetics of metalo-beta-lactamase in a new enzymatic system, the glyoxalase I and II in order to evaluate selectivity. (AU)

Scientific publications

(7)

(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)

MARTINS, PAULA; MACHADO, DAISY; THEIZEN, THAIS HOLTZ; OLIVEIRA GUARNIERI, JOAO PAULO; BERNARDES, BRUNO GAIA; GOMIDE, GABRIEL PICCIRILLO; FINZI CORAT, MARCUS ALEXANDRE; ABBEHAUSEN, CAMILLA; PROENCA MODENA, JOSE LUIZ; ODIR RODRIGUES MELO, CARLOS FERNANDO; et al. Outer Membrane Vesicles from Neisseria Meningitidis (Proteossome) Used for Nanostructured Zika Virus Vaccine Production. SCIENTIFIC REPORTS, v. 8, MAY 29 2018. (16/17066-2, 17/12719-0, 14/14457-5)

ABBEHAUSEN, C.. Zinc finger domains as therapeutic targets for metal-based compounds - an update. METALLOMICS, v. 11, n. 1, p. 15-28, JAN 1 2019. (17/12719-0)

E SILVA, MARIA DAS G. DE O.; GALUPPO, CAROLINA; TUDISCO, BARBARA C.; DE OLIVEIRA JUNIOR, ARNALDO G.; BARRIONUEVO, MANOEL V. F.; ABBEHAUSEN, CAMILLA; BUFFON, REGINA. Synthesis and characterization of a palladium(0) complex with cyclophosphazene bearing two diphenylphosphine ligands and application in Suzuki-Miyaura cross-coupling. Inorganica Chimica Acta, v. 482, p. 259-267, OCT 1 2018. (17/12719-0)

GOMES, S. Q.; VITORIANO, L.; DE ARRUDA, E. G. R.; RUIZ, A. L. T. G.; CANDIDO, T.; DE CARVALHO, J. E.; LUSTRI, W. R.; ABBEHAUSEN, C.. Linear gold(I) complex with tris-(2-carboxyethyl)phosphine (TCEP): Selective antitumor activity and inertness toward sulfur proteins. Journal of Inorganic Biochemistry, v. 186, p. 104-115, SEP 2018. (15/09833-0, 17/12719-0)

ADALSTEINSSON, HEIDAR MAR; LIMA, FREDERICO A.; GALUPPO, CAROLINA; ABBEHAUSEN, CAMILLA. Evaluation of cobalt complexes with tripod ligands for zinc finger targeting. DALTON TRANSACTIONS, v. 49, n. 45, p. 16143-16153, DEC 7 2020. (17/12719-0, 19/16904-2)

GALUPPO, CAROLINA; ALVARENGA, JAQUELINE; QUEIROZ, ADRIANA C.; MESSIAS, IGOR; NAGAO, RAPHAEL; ABBEHAUSEN, CAMILLA. The electrosynthesis of gold(I) complexes: A clean, one-pot method. Electrochemistry Communications, v. 110, JAN 2020. (17/12719-0, 16/01817-9, 17/11986-5)

TELES, C. M.; LAMMOGLIA, L. C.; JULIANO, M. A.; RUIZ, A. L. T. G.; CANDIDO, T. Z.; DE CARVALHO, J. E.; LIMA, C. S. P.; ABBEHAUSEN, C.. Novel anticancer Pd-II complexes: The effect of the conjugation of transferrin binding peptide and the nature of halogen coordinated on antitumor activity. Journal of Inorganic Biochemistry, v. 199, OCT 2019. (17/12719-0, 18/13588-0, 16/07729-4)