Antibiotic resistance is a serious and growing problem in the management of bacterial infectious disease. Bacterial species have evolved multiple mechanisms to overcome the action of antimicrobials (1). For example, some bacteria produce enzymes that modify or destroy the drug itself. This mechanism can cause an entire class of antibiotics to lose its effectiveness. The aminoglycoside family of antibiotics, initially discovered in the 1940’s, has been rendered nearly obsolete by enzymes found in numerous bacterial species. These enzymes include aminoglycoside acetyltransferases, nucleotidyltransferases, and phosphotransferases.
In collaboration with Dr. Gerry Wright at McMaster University in Hamilton, Ontario, Canada, researchers of the Center for Structural Genomics of Infectious Diseases (CSGID), have determined the structure of the aminoglycoside phosphotransferase (APH) enzyme APH(2")-IVa complexed with a small molecule inhibitor (2) (PDB entry 4DFU). The collaboration used a high-throughput screen of a library of small molecules known to inhibit similar proteins to identify inhibitors of APH enzymes, including the flavonoid quercetin. The APH(2")-IVa structure provided insights into the interactions between the inhibitor quercetin and the ATP-binding site of the enzyme. Using this and other inhibitor-bound structures of APH enzymes, researchers aim to develop therapies that block the action of resistance-conferring enzymes and restore susceptibility to this class of antibiotics.
For more information, please see the Protein Data Bank entry 4DFU.
Last Updated March 07, 2012
Last Reviewed March 07, 2012