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<p>The mycobacterial caseinolytic protease (Clp) system has been recognized as a promising therapeutic target. In this study, we identify two novel ilamycin analogs, ilamycin E (ILE) and ilamycin F (ILF), both targeting the ClpC1 component of the ClpC1P1P2 proteasome. ILE potently disrupts ClpC1P1P2-mediated proteolysis, leading to delayed bactericidal activity, while ILF also binds ClpC1, albeit with lower affinity. Notably, we discover and validate a unique mutation in <i>clpX</i> and a novel insertion in <i>clpC1</i> both conferring resistance to ILE and ILF in mycobacterium by gene editing. Furthermore, ILE can also inhibit the proteolytic activity of ClpXP1P2 in a manner dependent on the substrate’s tag sequence and adaptor. This first demonstration of <i>clpX</i>- and <i>clpC1</i>-mediated ilamycins resistance underscores the potential of ilamycins to target multiple components of the Clp protease system, offering a novel dual-target strategy for combating mycobacterial infections.</p>

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Mutations in ClpC1 or ClpX subunit of caseinolytic protease confer resistance to ilamycins in mycobacteria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月13日

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  • Yamin Gao,
  • Cuiting Fang,
  • Biao Zhou,
  • H. M. Adnan Hameed,
  • Changli Sun,
  • Xirong Tian,
  • Jing He,
  • Xingli Han,
  • Han Zhang,
  • Jun Li,
  • Jianhua Ju,
  • Xinwen Chen,
  • Nanshan Zhong,
  • Junying Ma,
  • Xiaoli Xiong,
  • Tianyu Zhang

摘要

The mycobacterial caseinolytic protease (Clp) system has been recognized as a promising therapeutic target. In this study, we identify two novel ilamycin analogs, ilamycin E (ILE) and ilamycin F (ILF), both targeting the ClpC1 component of the ClpC1P1P2 proteasome. ILE potently disrupts ClpC1P1P2-mediated proteolysis, leading to delayed bactericidal activity, while ILF also binds ClpC1, albeit with lower affinity. Notably, we discover and validate a unique mutation in clpX and a novel insertion in clpC1 both conferring resistance to ILE and ILF in mycobacterium by gene editing. Furthermore, ILE can also inhibit the proteolytic activity of ClpXP1P2 in a manner dependent on the substrate’s tag sequence and adaptor. This first demonstration of clpX- and clpC1-mediated ilamycins resistance underscores the potential of ilamycins to target multiple components of the Clp protease system, offering a novel dual-target strategy for combating mycobacterial infections.