2. Academic Validation
  3. Design, synthesis and optimization of TarO inhibitors as multifunctional antibiotics against Methicillin-resistant Staphylococcus aureus

Design, synthesis and optimization of TarO inhibitors as multifunctional antibiotics against Methicillin-resistant Staphylococcus aureus

  • NPJ Antimicrob Resist. 2025 Apr 12;3(1):28. doi: 10.1038/s44259-025-00098-z.
Yuanchen Zhong # 1 2,  Feifei Chen # 1 2 3,  Dianyan Chen 1 3,  Qian He 2,  Xiaofei Zhang 4 5,  Lefu Lan 6 7,  Chunhao Yang 8 9
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 310024, Hangzhou, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, 100049, Beijing, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China. xiaofeizhang@simm.ac.cn.
  • 5 University of Chinese Academy of Sciences, 100049, Beijing, China. xiaofeizhang@simm.ac.cn.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 310024, Hangzhou, China. llan@ucas.ac.cn.
  • 7 University of Chinese Academy of Sciences, 100049, Beijing, China. llan@ucas.ac.cn.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China. chyang@simm.ac.cn.
  • 9 University of Chinese Academy of Sciences, 100049, Beijing, China. chyang@simm.ac.cn.
  • # Contributed equally.
PMID: 40221595 DOI: 10.1038/s44259-025-00098-z
Abstract

UDP-N-acetylglucosamine-undecaprenyl-phosphate N-acetylglucosaminephosphotransferase (TarO) has been found to simultaneously contribute to β-lactam resistance and virulence of Methicillin-resistant Staphylococcus aureus (MRSA). However, optimization of hit compounds targeting TarO has been hindered due to their high lipophilicity and the poor correlation between the enzyme activity inhibition and β-lactam sensitization. In this study, 31 analogues of Tarocin A were designed, synthesized and evaluated by a luminescence-based reporter preliminary screening. In the subsequent β-lactams synergy test, a good correlation was observed between the results obtained from these two methods. Finally, analog 18a with more potential against TarO and an improved hydrophilicity (clogP = 3.2) was obtained. Compared with Tarocin A, 18a shows stronger β-lactam sensitizing and anti-biofilm activities in vitro, as well as potent anti-virulence and synergistic potency with imipenem in vivo. These results suggest that TarO is a promising target for combating MRSA, and 18a can serve as a lead molecule.

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