2. Academic Validation
  3. Discovery of potent ClpX modulators with pronounced antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)

Discovery of potent ClpX modulators with pronounced antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA)

  • Eur J Med Chem. 2026 Jan 5:301:118207. doi: 10.1016/j.ejmech.2025.118207.
Yan Liu 1,  Jin Li 1,  Yucheng Ma 2,  Wenfang Gao 1,  Yuanlong Li 3,  Jiangnan Zhang 1,  Baozhu Luo 1,  Jing Sui 1,  Tao Yang 4,  Yuan Ju 5,  Youfu Luo 6
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, China.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yangtao@wchscu.cn.
  • 5 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yuan.ju@scu.edu.cn.
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: luo_youfu@scu.edu.cn.
PMID: 41046624 DOI: 10.1016/j.ejmech.2025.118207
Abstract

The high morbidity and mortality rates associated with invasive methicillin-resistant Staphylococcus aureus (MRSA) infections underscore the pressing need to develop novel Antibiotics. ClpX, functioning as a cochaperone protein of ClpP, has been identified as a crucial target in combating MRSA. In this study, we screened an in-house library and identified a small molecule compound, PFK-158, with high affinity for Staphylococcus aureus ClpX (Kd = 4.1 μM). Simultaneously, PFK-158 displayed potent activity against MRSA (MIC = 2 μg/mL, MBC = 8 μg/mL). Further optimization resulted in a novel α, β-unsaturated ketone bearing a quinolinyl group and a 2-bromophenyl substituent with comparable binding affinity for Staphylococcus aureus ClpX (Kd = 3.6 μM), and it showed enhanced Antibacterial activity against MRSA and lower propensity for inducing resistance. Significantly, the novel α, β-unsaturated ketone bearing a quinolinyl group and a 2-bromophenyl substituent demonstrated favorable in vivo safety, oral bioavailability (F = 37.9 %), and promising therapeutic effects in a MRSA-infected skin abscess model. Overall, our findings presented a novel SaClpX modulator with the potential to combat Staphylococcus infections, and suggested a promising strategy for the further development of specific Staphylococcus aureus ClpX modulators.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z