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
  • 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. [email protected].
  • 5. University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
  • 6. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 310024, Hangzhou, China. [email protected].
  • 7. University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
  • 8. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, China. [email protected].
  • 9. University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
  • # 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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