Mycobacterium tuberculosis curli pili facilitates pathogenicity by modulating central carbon metabolism

TL;DR

This study shows that Mycobacterium tuberculosis curli pili (MTP) influences bacterial metabolism and energy production, making it a promising target for TB diagnostics and treatments.

Contribution

The study reveals MTP's role in regulating Mtb's central carbon metabolism and bioenergetics, a novel insight into TB pathogenicity.

Findings

MTP increases bacterial respiration and reduces glycolytic carbon catabolism when ATP synthase is inhibited.

Mtb Δmtp mutants rely more on oxidative phosphorylation for energy compared to wildtype strains.

Deletion of MTP disrupts central carbon metabolism pathways like glycolysis and the TCA cycle.

Abstract

Strategies specifically targeting the initial host–pathogen interactions, hold great promise in the identification of accurate biomarkers for tuberculosis (TB) prevention interventions. Mycobacterium tuberculosis (Mtb) curli pili (MTP) (encoded by mtp/Rv3312A), a surface adhesin utilised by the pathogen to interact with host receptor cells, has been reported as a suitable target for TB diagnostic and therapeutic strategies. Previous “omics” studies highlighted the role MTP potentially plays in Mtb central carbon metabolism (CCM). However, its precise contribution to metabolism remains unknown.

This study aimed to examine the role of MTP in the bioenergetic metabolism of Mtb, using bedaquiline (BDQ) to inhibit ATP production through oxidative phosphorylation (OXPHOS), extracellular flux analysis, Mtb wildtype (WT), ∆mtp deletion mutant, and mtp-complemented strains. The role of MTP in regulation of CCM was assessed using 13C6-metabolic flux analysis.

MTP was associated with increased bacterial respiration and decreased carbon catabolism via glycolysis in response to the inhibition of ATP synthase by BDQ. The dependence of Mtb Δmtp on OXPHOS for energy production was demonstrated to be greater than the WT and mtp-complemented strains. In addition, metabolic flux profiles revealed that in the Δmtp mutant, CCM was dysregulated by decreasing flux through glycolysis, tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism, and the pentose phosphate pathway in comparison to the WT.

These novel findings show that MTP is associated with the regulation of bioenergetics and metabolism pathways and substantiate MTP as a potential biomarker for TB diagnostics/therapeutics, and a novel target for vaccine/drug development.

The online version contains supplementary material available at 10.1007/s11306-025-02320-5.

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