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Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Prokaryotic Substrate-Binding Proteins as Targets for Antimicrobial Therapies

Author(s): Rafael M. Counago, Christopher A. McDevitt, Miranda P. Ween and Bostjan Kobe

Volume 13, Issue 11, 2012

Page: [1400 - 1410] Pages: 11

DOI: 10.2174/138945012803530170

Price: $65


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), transbilayer movement, periplasmic space.

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