StreptoMANIAC SIGNED

Project "StreptoMANIAC" data sheet

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 Project objective

The widespread emergence of acquired resistance to antibiotics constitutes a serious threat to global public health. Among Gram-positive pathogens, Streptococcus pneumoniae (the pneumococcus) is a normal resident of the oral and nasal cavities but is also cause of otitis media and sinusitis as well as pneumonia, bacteremia and meningitis, particularly in young children and the elderly. Despite the availability of effective vaccines, S. pneumoniae remains an important clinical problem, also because of the increase of multi-drug resistant clinical isolates. S. pneumoniae is, indeed, listed by the WHO as one of the priority pathogens to drive research, discovery and development of new antibiotics. In S. pneumoniae, resistance to beta-lactam antibiotics represents a highly complex scenario, involving both target enzymes, the penicillin-binding proteins (PBPs), and non-PBP components, as the two-component system CiaRH. In clinical isolates, beta-lactam resistance is primarily mediated by the acquisition of multiple mutations in the transpeptidase domain of three of its six PBPs: PBP2x, PBP2b and PBP1a. These modified PBPs have reduced affinity for beta-lactams while leaving the enzyme function unaffected, thus conferring an advantage for the mutated strains in the presence of the antibiotics. However, PBPs are not only the beta-lactam target but are also essential enzymes involved the last stages of peptidoglycan biosynthesis, where they play specific roles in peripheral (side-wall) growth and cell division. Whereas the majority of studies so far concentrated solely on the effect of altered PBPs on resistance, little is known about the impact of the altered PBPs on PG biosynthesis, cell growth and division. Using a combination of genetic, biochemical, cytological and comparative genomics techniques, this study aims to fill in the knowledge gaps in the cost and benefit of acquired beta-lactam resistance in S. pneumoniae and in the complex mechanisms that regulate it.