Fighting bacterial resistance: are coordination compounds an options for the metal...
| Grant number: | 17/12719-0 |
| Support type: | Regular Research Grants |
| Duration: | September 01, 2017 - August 31, 2019 |
| Field of knowledge: | Physical Sciences and Mathematics - Chemistry |
| Principal Investigator: | Camilla Abbehausen |
| Grantee: | Camilla Abbehausen |
| Home 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 |
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)