Aminoacyl-tRNA synthetase inhibitors as antimicrobial agents: a patent review from 2006 till present.
BACKGROUND
Aminoacyl-tRNA synthetases (aaRSs) are one of the leading targets for development of antimicrobial agents. Although these enzymes are well conserved among prokaryotes, significant divergence has occurred between prokaryotic and eukaryotic aaRSs, which can be exploited in the discovery of broad-spectrum antibacterial agents. Although several aaRS inhibitors have been reported before, they failed as a result of poor selectivity and limited cell penetration.


METHODS
This review covers January 2006 to April 2012 wherein several new analogues were claimed as aaRS inhibitors. Anacor Pharmaceuticals patented several boron-containing derivatives inhibiting the function of the editing domain of aaRSs. Two patents describe the combination of aaRS inhibitors with other antibacterial agents. Patents disclosing aaRS inhibitors for indications other than antimicrobial agents are not considered for review here.


CONCLUSIONS
Several recently disclosed leads may form the foundation for development of potent and selective bacterial aaRS inhibitors. In comparison with, for example, terbinafine and itraconazole, compound C10 (AN2690) is a very promising candidate for treatment of ungual and periungual infections with improved nail penetration and low keratin binding. In addition, Raplidyne, Inc. reported bicyclic heteroaromatic compounds as potent and selective inhibitors of bacterial MetRS. These have proven to be particularly effective for treatment of Clostridium difficile-associated diarrhea. Finally, combination of aaRS inhibitors to attenuate resistance looks as a viable strategy to expand the lifespan of existing antibiotics.
KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Bharat
B
Gadakh
Arthur
A
Van Aerschot
D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D010330:Patents as Topic; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D000604:Amino Acyl-tRNA Synthetases