Activation of L-histidine biosynthesis as a new antibiotic strategy against Mycobacterium tuberculosis
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Deborah 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 Gutierrez Luiz Pedro S de CarvalhoAbstract
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.
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Nature Communications
Volume
17
Pages
2795
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10.1038/s41467-026-70510-3
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Europe PubMed Central
41864986
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41864986
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The publication was previously a preprint.
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