Activation of L-histidine biosynthesis as a new antibiotic strategy against Mycobacterium tuberculosis.
- 2026-03-21
- Nature communications 17(1)
- PubMed: 41864986
- DOI: 10.1038/s41467-026-70510-3
Study Design
- Methods
- Engineered variants of Mycobacterium tuberculosis ATP-phosphoribosyltransferase that are resistant to allosteric inhibition by L-histidine, leading to supraphysiological activation and L-histidine overproduction
- Rigorous Journal
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.
Research Insights
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