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

TL;DR

This paper introduces a new antibiotic strategy that kills tuberculosis bacteria by overactivating a biochemical pathway, causing energy and nutrient depletion.

Contribution

The study demonstrates that activating, rather than inhibiting, a metabolic pathway can be an effective antimycobacterial strategy.

Findings

Supraphysiological activation of L-histidine biosynthesis reduces M. tuberculosis growth in culture.

Allosteric variants of ATP-PRT cause nutrient and energy depletion, leading to loss of bacterial fitness.

Expression of these variants reduces M. tuberculosis infections in human macrophages and mice.

Abstract

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.

Here, the authors report metabolic activation as a potential antimicrobial strategy against Mycobacterium tuberculosis. They show that supra-physiological activation of L-histidine biosynthesis reduces bacterial growth and causes loss of fitness due to nutrient and energy depletion.

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