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Analysis of inhibitors of the homologous recombination in ribosomal mutations associated with linezolid resistance in Gram-positive cocci

Grant number: 14/27267-0
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): August 14, 2015
Effective date (End): August 13, 2016
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal researcher:Elsa Masae Mamizuka
Grantee:Lara Mendes de Almeida
Supervisor abroad: Michael S. Gilmore
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Harvard University, Boston, United States  
Associated to the scholarship:12/16108-2 - Analysis of the effects of inhibitors of homologous recombination in ribosomal mutations involved in resistance to linezolid in Gram-positive cocci, BP.PD


Linezolid, a synthetic antimicrobial of the oxazolidinone class, is active against important bacterial pathogens, including multi-drug resistant Staphylococcus spp and Enterococcus spp. This new oxazolidinone drug inhibits protein biosynthesis by binding itself to the peptidyl transferase center (PTC) of the 50S subunit of the bacterial ribosome. Although linezolid resistance can be mediated by the cfr-encoded product or by mutations in the ribosomal proteins L3, L4 and L22, mutations in the central loop of domain V of the 23S rRNA gene are the most common mechanism of resistance, G2576T being reported more frequently in linezolid-resistant clinical isolates. A correlation between the increased number of mutated rRNA operons and high levels of minimum inhibitory concentrations (MIC) for linezolid has been found and the RecA-mediated gene conversion may be responsible for the conversion of wild-type alleles into mutant alleles. We will evaluate different serum concentrations of linezolid in combination with inhibitors of a homologous re-combination and compare the mRNA expression of the recA gene in different clinical strains. Furthermore, the whole genome sequencing of a linezolid-resistant S. haemolyticus strain having an unknown mechanism of resistance and its susceptible derivative will be compared to elucidate the cause of resistance to linezolid. The genetic environment surrounding the cfr gene of the linezolid-resistant E. faecalis strains which we recently identified in different states of Brazil will also be investigated as well as the genomic background of some linezolid-resistant isolates from humans and animals. (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)
ALMEIDA, LARA M.; LEBRETON, FRANCOIS; GACA, ANTHONY; BISPO, PAULO M.; SAAVEDRA, JOSE T.; CALUMBY, RODRIGO N.; GRILLO, LUCIANO M.; NASCIMENTO, TICIANO G.; FILSNER, PEDRO H.; MORENO, ANDREA M.; GILMORE, MICHAEL S. Transferable Resistance Gene optrA in Enterococcus faecalis from Swine in Brazil. Antimicrobial Agents and Chemotherapy, v. 64, n. 6 JUN 2020. Web of Science Citations: 0.

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