6p3t | pdb_00006p3t
Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT449
Structural highlights
FunctionEIS_MYCTU May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.[1] Publication Abstract from PubMedEach year, millions of people worldwide contract tuberculosis (TB), the deadliest infection. The spread of infections with drug-resistant strains of Mycobacterium tuberculosis (Mtb) that are refractory to treatment poses a major global challenge. A major cause of resistance to antitubercular drugs of last resort, aminoglycosides, is overexpression of the Eis (enhanced intracellular survival) enzyme of Mtb, which inactivates aminoglycosides by acetylating them. We showed previously that this inactivation of aminoglycosides could be overcome by our recently reported Eis inhibitors that are currently in development as potential aminoglycoside adjunctive therapeutics against drug-resistant TB. To interrogate the robustness of the Eis inhibitors, we investigated the enzymatic activity of Eis and its inhibition by Eis inhibitors from three different structural families for nine single-residue mutants of Eis, including those found in the clinic. Three engineered mutations of the substrate binding site, D26A, W36A, and F84A, abolished inhibitor binding while compromising Eis enzymatic activity 2- to 3-fold. All other Eis mutants, including clinically observed ones, were potently inhibited by at least one inhibitor. This study helps position us one step ahead of Mtb resistance to Eis inhibitors as they are being developed for TB therapy. Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis.,Green KD, Punetha A, Hou C, Garneau-Tsodikova S, Tsodikov OV ACS Infect Dis. 2019 Oct 11;5(10):1772-1778. doi: 10.1021/acsinfecdis.9b00228., Epub 2019 Aug 21. PMID:31433614[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
