Browsing by Author "Lee, Bei Shi"

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Dual inhibition of the terminal oxidases eradicates antibiotic‐tolerant Mycobacterium tuberculosis
(EMBO, 2020-12) Lee, Bei Shi; Hards, Kiel; Engelhart, Curtis A.; Hasenoehrl, Erik J.; Kalia, Nitin P.; Mackenzie, Jared S.; Sviriaeva, Ekaterina; Chong, Shi Min Sherilyn; Manimekalai, Sony S.; Koh, Vanessa H.; Xu, Jiayong; Alonso, Sylvie; Miller, Marvin J.; Steyn, Adrie J.C.; Gruber, Gerhard; Schnappinger, Dirk; Berney, Michael; Cook, Gregory M.; Moraski, Garrett C.; Pethe, Kevin
The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotictolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.
Hydride-induced Meisenheimer complex formation reflects activity of nitro aromatic anti-tuberculosis compounds
(Royal Society of Chemistry, 2021-02) Liu, Rui; Markley, Lowell; Miller, Patricia A.; Franzblau, Scott; Shetye, Gauri; Ma, Rui; Savková, Karin; Mikušová, Katarína; Lee, Bei Shi; Pethe, Kevin; Moraski, Garrett C.; Miller, Marvin J.
The formation efficiency of hydride-induced Meisenheimer complexes of nitroaromatic compounds is consistent with their anti-TB activities exemplied by MDL860 and benzothiazol N-oxide (BTO) analogs. Herein we report that nitro cyano phenoxybenzenes (MDL860 and analogs) reacted slowly and incompletely which reflected their moderate anti-TB activity, in contrast to the instantaneous reaction of BTO derivatives to quantitatively generate Meisenheimer complexes which corresponded to their enhanced anti-TB activity. These results were corroborated by mycobacterial and radiolabelling studies that confirmed inhibition of the DprE1 enzyme by BTO derivatives but not MDL860 analogs.
Structure guided generation of thieno[3,2-d]pyrimidin-4-amine Mycobacterium tuberculosis bd oxidase inhibitors
(Royal Society of Chemistry, 2021-01) Hopfner, Sarah M.; Lee, Bei Shi; Kalia, Nitin P.; Miller, Marvin J.; Pethe, Kevin; Moraski, Garrett C.
Screening for inhibitors of Cyt-bd in Mycobacterium bovis BCG and Mycobacterium tuberculosis revealed thieno[3,2-d]pyrimidine (7) which through SAR efforts resulted in an improved analogue (19) of this scaffold.
Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis
(MDPI, 2021-09) Hopfner, Sarah M.; Lee, Bei Shi; Kalia, Nitin P.; Miller, Marvin J.; Pethe, Kevin; Moraski, Garrett C.
The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D.