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Development of new antibiotics against super-resistant Staphylococcus aureus strains: identification and characterization of inhibitors of the enzyme Diadenylate cyclase

Abstract

Recently, a nucleotide-based molecule, cyclic dimeric adenosine monophosphate (c-di-AMP), has been identified in several pathogenic bacteria, rapidly gaining the status of a central signaling controlling several essential bacterial processes, such as ion transport and DNA damage surveillance. In Staphylococcus aureus, it was found that c-di-AMP is essential for the cell wall homeostasis and resistance against environmental stresses. Similar to most studied signaling pathways mediated by c-di-GMP, the biosynthesis of c-di-AMP involves the antagonistic enzymatic activities of specific cyclases and phosphodiesterases specific from the domain families DAC (diadenylate cyclase) and DHH/DHHA1, respectively. Although the structure of a DNA integrity scanning protein (DisA), which possesses an active DAC domain, has already been determined, little is known about the activation of these enzymes and even the catalytic mechanism of this domain. Our group recently determined the structure of the single enzyme from S. aureaus and revealed its catalytic mechanism. This project extends the knowledge accumulated in the group, and aims to implement appropriate enzymatic assays for automated processes in order to identify specific inhibitors of Sa_DacA, using different libraries of compounds. Bioactive compounds identified in these high-throughput screenings will be further characterized with respect to mechanisms of inhibition and inhibitory potency. It is also expected the structural determination of enzyme-inhibitor complexes to gain insights about the determinants of molecular recognition. In vivo tests will be implemented to assess the bactericidal or bacteriostatic activity of the inhibitors identified against super-resistant strains of S. aureus. The results generated in this project can serve as a basis for future development and studies of new antibiotics, which in combination with currently available treatments could control the infections caused even by the most resistant forms of S. aureus. (AU)

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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)
SASTRE, DIEGO E.; PULSCHEN, ANDRE A.; BASSO, LUIS G. M.; PARIENTE, JHONATHAN S. BENITES; MARQUES NETTO, CATERINA G. C.; MACHINANDIARENA, FEDERICO; ALBANESI, DANIELA; NAVARRO, MARCOS V. A. S.; DE MENDOZA, DIEGO; GUEIROS-FILHO, FREDERICO J. The phosphatidic acid pathway enzyme PlsX plays both catalytic and channeling roles in bacterial phospholipid synthesis. Journal of Biological Chemistry, v. 295, n. 7, p. 2148-2159, FEB 14 2020. Web of Science Citations: 1.
SASTRE, DIEGO E.; BASSO, LUIS G. M.; TRASTOY, BEATRIZ; CIFUENTE, JAVIER O.; CONTRERAS, XABIER; GUEIROS-FILHO, FREDERICO; DE MENDOZA, DIEGO; NAVARRO, MARCOS V. A. S.; GUERIN, MARCELO E. Membrane fluidity adjusts the insertion of the transacylase PlsX to regulate phospholipid biosynthesis in Gram-positive bacteria. Journal of Biological Chemistry, v. 295, n. 7, p. 2136-2147, FEB 14 2020. Web of Science Citations: 2.

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