Mycobacterium tuberculosis curli pili facilitates pathogenicity by modulating central carbon metabolism.

Introduction: 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.

Objectives: 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.

Results: 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.

Conclusion: 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.