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<p>UDP-<i>N</i>-acetylglucosamine-undecaprenyl-phosphate <i>N</i>-acetylglucosaminephosphotransferase (TarO) has been found to simultaneously contribute to β-lactam resistance and virulence of Methicillin-resistant <i>Staphylococcus aureus</i> (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 <b>18a</b> with more potential against TarO and an improved hydrophilicity (clogP = 3.2) was obtained. Compared with Tarocin A, <b>18a</b> 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 <b>18a</b> can serve as a lead molecule.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月12日

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  • Yuanchen Zhong,
  • Feifei Chen,
  • Dianyan Chen,
  • Qian He,
  • Xiaofei Zhang,
  • Lefu Lan,
  • Chunhao Yang

摘要

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.