ACS Medicinal Chemistry Letters· 2026Q1
Design, Synthesis, and Antimicrobial Activity of Novel Cyt- bd Inhibitors Targeting Energy Compensation in Mycobacterium tuberculosis
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- Q1SCImago
- 2026year
Short summary
A novel compound, YH-685, potently inhibits the alternative cytochrome bd oxidase (Cyt-bd) in Mycobacterium tuberculosis (Mtb) with an IC50 of 0.45 μM, and when combined with a Cyt-bcc inhibitor, it suppressed virulent Mtb growth in macrophages, achieving inhibition comparable to standard regimens.
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Key points
- A new compound, YH-685, was designed and synthesized as a potent inhibitor of the Mycobacterium tuberculosis Cyt-bd oxidase (IC50 = 0.45 μM).
- YH-685 demonstrates potent inhibition against Cyt-bcc deficient Mycobacterium smegmatis (MIC = 0.8 μM).
- The combination of YH-685 with a Cyt-bcc inhibitor (TB47) effectively suppressed virulent Mtb H37Rv in human macrophages.
- This combination therapy achieved growth inhibition comparable to standard regimens (rifampicin–isoniazid and bedaquiline) in vitro.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Drug-resistant Mycobacterium tuberculosis (Mtb) poses a growing threat, necessitating new therapeutic strategies. The cytochrome bcc-aa3 oxidase (Cyt-bcc) is an attractive target, yet single-agent inhibition fails owing to compensation by the alternative cytochrome bd terminal oxidase (Cyt-bd). Herein, we describe a structure–activity relationship (SAR) study starting from the previously identified Cyt-bd inhibitor 12, leading to the discovery of 17aa (YH-685). YH-685 potently inhibits Cyt-bcc deficient Mycobacterium smegmatis (Δbcc) with a MIC of 0.8 μM and suppresses Cyt-bd dependent oxygen consumption in inverted membrane vesicles with an IC50 of 0.45 μM. When combined with the Cyt-bcc inhibitor TB47, YH-685 enhanced inhibition of virulent Mtb H37Rv, reducing both planktonic growth and intracellular bacterial burdens in human macrophages, as assessed by high-content imaging. Under the tested in vitro conditions, this combination achieved growth inhibition comparable to standard regimens rifampicin–isoniazid and bedaquiline. Our study supports co-targeting Cyt-bd and Cyt-bcc as a therapeutic strategy for drug-resistant tuberculosis.
The authors' abstract, as published at the source. ACS Medicinal Chemistry Letters, 2026 · DOI ↗
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Field: Infectious Diseases
Infectious DiseasesMedicine