# 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.

## Key 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.