Activation of l-histidine biosynthesis as a new antibiotic strategy against Mycobacterium tuberculosis
- 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
2026-03-21
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.