Bacterial resistance to clinically important antibacterial agents represents a crucial and worldwide health-care problem.1 New strategies are needed to combat resistant pathogens and to avoid the increasing prevalence of multi-drug resistant (MDR) bacteria. Among the strategies by which the bacteria develop the resistance to antibiotics, overexpression of the efflux pumps provides a self-defense mechanism by which antibiotics are actively removed from the cell. For antibacterials, this results in sublethal drug concentrations at the target, that in turn may predispose for the development of high-level target-based resistance. Therefore, efflux pumps are viable antibacterial targets, and identification and development of potent Efflux Pump Inhibitors (EPIs) is a promising and valid strategy which can restore the susceptibility of resistant strains to antibacterial agents that are substrates of efflux pumps.2 Methicillin-resistant Staphylococcus aureus (MRSA) is a MDR bacteria which represent the major cause of healthcare-associated infection (HAIs) in the EU. In 2008, MRSA accounted for 44% of HAIs and 22% of attributable extra deaths.3 The increased expression of one or more MDR efflux pump genes was identified in 49% of the S. aureus clinical strains. Among those, norA was the most common (43%), followed by norB (23.2%) and mepA (9.9%).4 NorA is the most studied efflux pump of the S. aureus and confers to such MDR bacteria the decreased susceptibility to many structurally unrelated agents, including fluoroquinolones. Different classes of NorA EPIs have been described by our research group during the last years.5-10 Among these, the most promising classes are: the 3-phenyl-1,4- benzothiazines,5 the 6-amino-7-thiopyranopyridinylquinolone ethyl esters,6 the 2-(4-propoxyphenyl)quinolines,8 and the pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide derivatives.10 In this contribution, an overview of our work on the discovery of NorA EPIs, as well as the most interesting updates, will be given.

S. aureus NorA efflux pump: the discovery of new potent inhibitors

GOSETTO, FRANCESCA;SABATINI, STEFANO;TABARRINI, Oriana;CECCHETTI, Violetta
2012-01-01

Abstract

Bacterial resistance to clinically important antibacterial agents represents a crucial and worldwide health-care problem.1 New strategies are needed to combat resistant pathogens and to avoid the increasing prevalence of multi-drug resistant (MDR) bacteria. Among the strategies by which the bacteria develop the resistance to antibiotics, overexpression of the efflux pumps provides a self-defense mechanism by which antibiotics are actively removed from the cell. For antibacterials, this results in sublethal drug concentrations at the target, that in turn may predispose for the development of high-level target-based resistance. Therefore, efflux pumps are viable antibacterial targets, and identification and development of potent Efflux Pump Inhibitors (EPIs) is a promising and valid strategy which can restore the susceptibility of resistant strains to antibacterial agents that are substrates of efflux pumps.2 Methicillin-resistant Staphylococcus aureus (MRSA) is a MDR bacteria which represent the major cause of healthcare-associated infection (HAIs) in the EU. In 2008, MRSA accounted for 44% of HAIs and 22% of attributable extra deaths.3 The increased expression of one or more MDR efflux pump genes was identified in 49% of the S. aureus clinical strains. Among those, norA was the most common (43%), followed by norB (23.2%) and mepA (9.9%).4 NorA is the most studied efflux pump of the S. aureus and confers to such MDR bacteria the decreased susceptibility to many structurally unrelated agents, including fluoroquinolones. Different classes of NorA EPIs have been described by our research group during the last years.5-10 Among these, the most promising classes are: the 3-phenyl-1,4- benzothiazines,5 the 6-amino-7-thiopyranopyridinylquinolone ethyl esters,6 the 2-(4-propoxyphenyl)quinolines,8 and the pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide derivatives.10 In this contribution, an overview of our work on the discovery of NorA EPIs, as well as the most interesting updates, will be given.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/888300
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