Resistance in In Vitro Selected Tigecycline-Resistant Methicillin-Resistant Staphylococcus aureus Sequence Type 5 Is Driven by Mutations in mepR and mepA Genes

Autor(es)

Gebieluca Dabul, Andrei Nicoli ^[1] ; Avaca-Crusca, Juliana Sposto ^[1] ; Van Tyne, Daria ^{[2, 3]} ; Gilmore, Michael S. ^{[2, 3]} ; Baratella Cunha Camargo, Ilana Lopes ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sao Carlos Inst Phys, Dept Phys & Interdisciplinary Sci, POB 369, BR-13560970 Sao Carlos, SP - Brazil

^[2] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA - USA

^[3] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA - USA

• Tipo de documento: Artigo Científico
• Fonte: MICROBIAL DRUG RESISTANCE; v. 24, n. 5, p. 519-526, JUN 2018.
• Citações Web of Science: 9

Resumo

A tigecycline-susceptible (TGC-S) Sequence Type (ST) 5 clinical methicillin-resistant Staphylococcus aureus (MRSA) strain was cultured in escalating levels of tigecycline, yielding mutants eightfold more resistant. Their genomes were sequenced to identify genetic alterations, resulting in resistance. Alterations in rpsJ, commonly related to tigecycline resistance, were also investigated. Tigecycline resistance was mediated by loss-of-function mutations in the transcriptional repressor mepR, resulting in derepression of the efflux pump mepA. Increased levels of resistance were obtained by successive mutations in mepA itself. No alterations in RpsJ were observed in selected strains, but we observed a K57M substitution, previously correlated with resistance, among TGC-S clinical strains. Thus, the pathway to tigecycline resistance in CC5 MRSA in vitro appears to be derepression of mep operon as the result of mepR loss-of-function mutation, followed by alterations in MepA efflux pump. This shows that other evolutionary pathways, besides mutation of rpsJ, are available for evolving tigecycline resistance in CC5 MRSA. (AU)

• Processo FAPESP: 10/02619-0 - Estudo epidemiológico molecular de Staphylococcus aureus resistentes à meticilina (MRSA) isolados no Brasil e estudo da proteína reguladora de resposta GraR
• Beneficiário: Ilana Lopes Baratella da Cunha Camargo
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/24952-0 - Padrões da emergência de enterococci e staphylococci multiresistentes no Brasil e busca por novos fármacos
• Beneficiário: Andrei Nicoli Gebieluca Dabul Dias de Sousa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado