TY - JOUR
T1 - Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors
AU - Garzan, Atefeh
AU - Willby, Melisa J.
AU - Ngo, Huy X.
AU - Gajadeera, Chathurada S.
AU - Green, Keith D.
AU - Holbrook, Selina Y.L.
AU - Hou, Caixia
AU - Posey, James E.
AU - Tsodikov, Oleg V.
AU - Garneau-Tsodikova, Sylvie
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/4/14
Y1 - 2017/4/14
N2 - Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.
AB - Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.
KW - aminoglycoside acetyltransferase
KW - bacterial resistance
KW - drug combination
KW - enzyme inactivation
KW - structure-activity-relationship analysis
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U2 - 10.1021/acsinfecdis.6b00193
DO - 10.1021/acsinfecdis.6b00193
M3 - Article
C2 - 28192916
AN - SCOPUS:85017563945
VL - 3
SP - 302
EP - 309
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 4
ER -
