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
  • 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: [email protected].
  • 5. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 6. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
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.

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