Structural highlights
Function
[EIS_MYCTU] May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.[1]
Publication Abstract from PubMed
A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.
Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis.,Willby MJ, Green KD, Gajadeera CS, Hou C, Tsodikov OV, Posey JE, Garneau-Tsodikova S ACS Chem Biol. 2016 Apr 7. PMID:27010218[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wei J, Dahl JL, Moulder JW, Roberts EA, O'Gaora P, Young DB, Friedman RL. Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol. 2000 Jan;182(2):377-84. PMID:10629183
- ↑ Willby MJ, Green KD, Gajadeera CS, Hou C, Tsodikov OV, Posey JE, Garneau-Tsodikova S. Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis. ACS Chem Biol. 2016 Apr 7. PMID:27010218 doi:http://dx.doi.org/10.1021/acschembio.6b00110
