TY - JOUR
T1 - Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from Mycobacterium tuberculosis
AU - Punetha, Ankita
AU - Ngo, Huy X.
AU - Holbrook, Selina Y.L.
AU - Green, Keith D.
AU - Willby, Melisa J.
AU - Bonnett, Shilah A.
AU - Krieger, Kyle
AU - Krieger, Kyle
AU - Dennis, Emily K.
AU - Posey, James E.
AU - Parish, Tanya
AU - Parish, Tanya
AU - Tsodikov, Oleg V.
AU - Tsodikov, Oleg V.
AU - Garneau-Tsodikova, Sylvie
AU - Garneau-Tsodikova, Sylvie
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/6/19
Y1 - 2020/6/19
N2 - The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design.
AB - The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design.
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U2 - 10.1021/acschembio.0c00184
DO - 10.1021/acschembio.0c00184
M3 - Article
C2 - 32421305
AN - SCOPUS:85085694315
SN - 1554-8929
VL - 15
SP - 1581
EP - 1594
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 6
ER -
