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<p>The increasing prevalence of antimicrobial resistance is an important challenge that warrants new approaches to antibiotic development. Currently, all antibiotics inhibit biological processes. To explore whether activation of a biochemical pathway can elicit bactericidal effects we engineered variants of <i>Mycobacterium tuberculosis</i> ATP-phosphoribosyltransferase (ATP-PRT) that are resistant to allosteric inhibition by <span>l</span>-histidine, leading to supraphysiological activation of ATP-PRT and <span>l</span>-histidine overproduction. Upregulation of L-histidine biosynthesis significantly reduces the growth of <i>M. tuberculosis</i> in culture and causes a loss of fitness owing to nutrient and energy depletion. Moreover, the expression of allosteric variants in <i>M. tuberculosis</i> significantly reduced infections in human macrophages and in a mouse model of infection. Thus, metabolic activation represents a new mycobactericidal mechanism that could be applied to antimycobacterial drug discovery.</p>

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Activation of l-histidine biosynthesis as a new antibiotic strategy against Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月21日

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  • Debbie M. Hunt,
  • João Pedro Pisco,
  • Angela Rodgers,
  • Cesira de Chiara,
  • Anisha Zaveri,
  • Kamila L. Pacholarz,
  • Dimitrios Evangelopoulos,
  • Acely Garza-Garcia,
  • Sabine Ehrt,
  • Dirk Schnappinger,
  • Perdita E. Barran,
  • Maximiliano G. Gutierrez,
  • Luiz Pedro S. de Carvalho

摘要

The increasing prevalence of antimicrobial resistance is an important challenge that warrants new approaches to antibiotic development. Currently, all antibiotics inhibit biological processes. To explore whether activation of a biochemical pathway can elicit bactericidal effects we engineered variants of Mycobacterium tuberculosis ATP-phosphoribosyltransferase (ATP-PRT) that are resistant to allosteric inhibition by l-histidine, leading to supraphysiological activation of ATP-PRT and l-histidine overproduction. Upregulation of L-histidine biosynthesis significantly reduces the growth of M. tuberculosis in culture and causes a loss of fitness owing to nutrient and energy depletion. Moreover, the expression of allosteric variants in M. tuberculosis significantly reduced infections in human macrophages and in a mouse model of infection. Thus, metabolic activation represents a new mycobactericidal mechanism that could be applied to antimycobacterial drug discovery.