Molecular mechanisms responsible for bacterial antibiotic-resistance: evaluation of new compounds, targets and strategies for the therapy of infections caused by multidrug-resistant pathogens Antimicrobial resistance is a growing problem that complicates the treatment of important nosocomial and community-acquired infections. Areas of focus include multidrug-resistant (MDR) bacteria in the hospital setting, such as Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus spp and the growing problem of community-acquired methicillin-resistant Staphylococcus aureus (www.rivm.nl/earss/result/Monitoring_reports/). Treatment of infections is compromised worldwide by the emergence of bacteria that are resistant to multiple antibiotics. Although classically attributed to chromosomal mutations, resistance is most commonly associated with extrachromosomal elements acquired from other bacteria in the environment. These include different types of mobile DNA segments, such as plasmids, transposons and integrons. However, intrinsic mechanisms not commonly specified by mobile elements - such as efflux pumps that expel multiple kinds of antibiotics - are now recognized as major contributors to multidrug resistance in bacteria.
The first aim of the present project is to characterize the “antibiotic resistome” (Wright GD, Nature Reviews in Microbiology, 2007) of pathogens isolated in the Northern Italy and characterized by particular resistance phenotypes. With a particular interest to fluoroquinolone agents, this will be conducted analysing several molecular mechanisms (DNA-gyrase and topoisomerasi IV genes modifications, active efflux systems, acetylation of susceptible compounds) that can participate, alone or together, in the cumulative antibiotic resistance. Moreover, the clonal diffusion of bacteria responsible of infections will be studied by the usage of the PFGE (Pulsed Field Gel Electrophoresis) method.
Moreover, one of the pressing goals to confront the twenty first century’s public health challenges brought about by the escalating antibacterial drug resistance problem is the development of an armamentarium of new chemotherapeutic agents.
A second aim of the project will be the evaluation of the "in vitro" antibacterial activity (MIC, MBC PAE, Killing-time and cellular viability determinations, bacterial morphology studies based on TEM and SEM microscopy) of new beta-lactams, glycosyl beta-lactams and adjuvant oligosaccharides designed and obtained by synthesis in order to have a better affinity for the modified PBPs of antibiotic-resistant Gram-positive bacteria.
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