Prokaryotic substrate-binding proteins as targets for antimicrobial therapies.
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.
Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
Rafael M
RM
Couñago
Christopher A
CA
McDevitt
Miranda P
MP
Ween
Bostjan
B
Kobe
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000472:pathogenicity; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011387:Prokaryotic Cells / Q000378:metabolism*; D013379:Substrate Specificity; D014774:Virulence
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins