RESUMO
The antibiotic fosfomycin (FOS) is widely recognized for the treatment of lower urinary tract infections with Escherichia coli and has lately gained importance as a therapeutic option to combat multidrug-resistant bacteria. However, resistance to FOS frequently develops through mutations reducing its uptake. Although the inner-membrane transport of FOS has been extensively studied in E. coli, its outer-membrane (OM) transport remains insufficiently understood. While evaluating minimal inhibitory concentrations in OM porin-deficient mutants, we observed that the E. coli ΔompFΔompC strain is four times more resistant to FOS than the wild type and the respective single mutants. Continuous monitoring of FOS-induced lysis of porin-deficient strains additionally highlighted the importance of LamB. The relevance of OmpF, OmpC, and LamB to FOS uptake was confirmed by electrophysiological and transcriptional analysis. Our study gives for the first time in-depth insight into the transport of FOS through the OM in E. coli.
Assuntos
Proteínas de Escherichia coli , Fosfomicina , Escherichia coli/genética , Escherichia coli/metabolismo , Fosfomicina/farmacologia , Transporte Biológico , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Porinas/genética , Porinas/metabolismoRESUMO
Background: Cardiovascular diseases (CVDs) pose a significant global health challenge, necessitating innovative approaches for primary prevention. Personalized prevention, based on genetic risk scores (PRS) and digital technologies, holds promise in revolutionizing CVD preventive strategies. However, the clinical efficacy of these interventions requires further investigation. This study presents the protocol of the INNOPREV randomized controlled trial, aiming to evaluate the clinical efficacy of PRS and digital technologies in personalized cardiovascular disease prevention. Methods: The INNOPREV trial is a four-arm RCT conducted in Italy. A total of 1,020 participants, aged 40-69 with high 10-year CVD risk based on SCORE 2 charts, will be randomly assigned to traditional CVD risk assessment, genetic testing (CVD PRS), digital intervention (app and smart band), or a combination of genetic testing and digital intervention. The primary objective is to evaluate the efficacy of providing CVD PRS information, measured at baseline, either alone or in combination with the use of an app and a smart band, on two endpoints: changes in lifestyle patterns, and modification in CVD risk profiles. Participants will undergo a comprehensive assessment and cardiovascular evaluation at baseline, with follow-up visits at one, five, and 12 months. Lifestyle changes and CVD risk profiles will be assessed at different time points beyond the initial assessment, using the Life's Essential 8 and SCORE 2, respectively. Blood samples will be collected at baseline and at study completion to evaluate changes in lipid profiles. The analysis will employ adjusted mixed-effect models for repeated measures to assess significant differences in the data collected over time. Additionally, potential moderators and mediators will be examined to understand the underlying mechanisms of behavior change. Discussion: As the largest trial in this context, the INNOPREV trial will contribute to the advancement of personalized cardiovascular disease prevention, with the potential to positively impact public health and reduce the burden of CVDs on healthcare systems. By systematically examining the clinical efficacy of PRS and digital interventions, this trial aims to provide valuable evidence to guide future preventive strategies and enhance population health outcomes.