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Fighting bacterial resistance: are coordination compounds an options for the metallo-beta-lactamase inhibition?

Grant number: 15/09905-1
Support type:Regular Research Grants
Duration: July 01, 2015 - June 30, 2017
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
Principal Investigator:Camilla Abbehausen
Grantee:Camilla Abbehausen
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

According to the data of World Health Organization the bacterial resistance to the antibacterial agents has affecting the advance of modern medicine. The ²-lactam compounds are the major family of drugs in the treatment of infections. However, the broad and misuse of these compounds triggered the evolution of the mechanisms of pathogen resistance. Among the described mechanisms the most important is the inactivation of the antibacterial drugs by the action of hydrolytic enzymes, called ²-lactamases. Several beta-lactamases were found and classified conform their structures. Inhibitors of ²-lactamases were associated to the antibacterial agents in an attempt to overcome the resistance mechanisms. However, one class emerged as a major threat to the treatment of infections, firstly because it hydrolyses almost all kinds of beta-lactam compounds and secondly there are no inhibitors for this class of enzymes, the class of metallo-²-lactamases. Differently of the other classes, it is based on zinc-enzymes. The inhibitors investigated so far present technical limitations to the clinical usage. Metal complexes has been successfully applied in the clinic, highlighting the anti tumor cis-diaminedichloroplatinum(II). Studies show that metals, in general, act as electrophiles on zinc coordinated residues and zinc-proteins has been considered as interesting biological targets for metal complexes. Thus, coordination compounds are presented as promising alternatives for the development of metallo-beta-lactamase inhibitors.In this proposal the interaction of the metal ions Pd(II), Pt(II), Au(I), Au(III) and Ag(I) and their complexes with metallo-²-lactamases are intended to be explored. The ability of inhibition of these enzymes by metals, and their complexes are going to be evaluated. In addition, mechanistic studies are proposed using mimetics and computational methods. (AU)

Scientific publications
(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)
FERRARESSO, L. G.; DE ARRUDA, E. G. R.; DE MORAES, T. P. L.; FAZZI, R. B.; FERREIRA, A. M. DA COSTA; ABBEHAUSEN, C. Copper(II) and zinc(II) dinuclear enzymes model compounds: The nature of the metal ion in the biological function. Journal of Molecular Structure, v. 1150, p. 316-328, DEC 15 2017. Web of Science Citations: 3.

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