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|Title:||Prokaryotic substrate-binding proteins as targets for antimicrobial therapies|
|Citation:||Current Drug Targets, 2012; 13(11):1400-1410|
|Publisher:||Bentham Science Publishers Ltd.|
|M. Counago, Rafael; A. McDevitt, Christopher; P. Ween, Miranda; Kobe, Bostjan|
|Abstract:||The rapid emergence of multidrug-resistant bacteria over the last two decades has catalyzed a shift away from traditional antibiotic development strategies and encouraged the search for unconventional drug targets. Prokaryotic substrate- binding proteins (SBPs), together with their cognate ATP-binding cassette (ABC) transporters, facilitate the unidirectional, transbilayer movement of specific extracytosolic cargoes against a concentration gradient, powered by ATP hydrolysis. In Gram-negative bacteria, SBPs are found in the periplasmic space, whereas in Gram-positive organisms these proteins are anchored to the outer cell wall by a lipid moiety. SBPs are vital components of the substrate-translocation machinery, as they determine cargo specificity and are involved in coupling the cargo uptake process with ABC transporter- mediated ATP hydrolysis. In this review, we focus on "Cluster A-1" divalent metal-binding proteins from within the SBP family. Acquisition of transition row metal ions is essential for bacterial colonization and virulence and Cluster A-1 SBPs play an integral role in this process. Cluster A-1 SBPs lack homologs in humans, bypass the need to deliver compounds into the bacterial cell, and are therefore potential drug targets against Gram-positive bacteria. Here we discuss the role SBPs play in the prokaryotic substrate-translocation machinery with emphasis in the substrate-binding mechanism of Cluster A-1 SBPs, the role of these proteins in virulence and their potential use as drug targets.|
|Keywords:||ABC transporter; ATP-binding cassette; antimicrobials; bacterial pathogens; Cluster A-1 SBP; drug design; metal binding; substrate-binding protein (SBP).|
|Rights:||© 2012 Bentham Science Publishers|
|Appears in Collections:||Molecular and Biomedical Science publications|
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