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Issue Date: 20-Feb-2013
Authors: Purrello, Simona Maria
Title: Multiple gene contribution to the phenotypic and genotypic Daptomycin non-susceptible (DNS) variants of Methicillin-Resistant Staphylococcus aureus isogenic strains
Abstract: Daptomycin (DAP) represents today a valid alternative choice in the treatment of multi-drug resistant (MDR) Staphylococcus aureus infections that do not respond to vancomycin therapy. Knowledge of clinical failure associated with DAP non-susceptibility (DNS) have been accounted in the USA and Europe, and the possibility of glycopeptide induction of low levels of DAP efficacy is worsening this scenario. The phenotypic alterations that characterize DNS S.aureus take place in changes in cell-wall arrangement, turnover, membrane structure and potential, and in modifications of cell autolysis and permeabilization. This study intended to analyze the molecular traits responsible for the phenotypic features of DNS strains, in three sets of isogenic clinical S.aureus in which DNS phenotype arise after DAP therapy. With regard to the genes involved in cell-wall charge, quantitative relative real time RT-PCR data revealed that mprF showed an up-regulation in DNS strains presenting a mprF mutation, whereas a down-regulation in DNS strains which not presented mutations. All DNS isolates had a dltA up-regulation, while both DNS and hDAP strains presented a cls2 up-regulation. Considering genes involved in the cell-wall turnover and autolysis, all DNS isolates exhibited high transcription levels of sceD and atl. Our data confirm the multi-factorial nature of DNS and suggest that the keystone of this phenotype is the mechanism of electrostatic repulsion and, indirectly, a reduction of autolysin activity due mainly to a dltA over expression-dependent, cls2-independent mechanism, as well as to the accumulation of additional secondary factors, such as the presence of mutations correlated with the increased levels of mprF transcription.
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