Mycobacterium tuberculosis curli pili (MTP) deficiency is associated with alterations in cell wall biogenesis, fatty acid metabolism and amino acid synthesis

Abstract

Introduction

In an effort to find alternative therapeutic interventions to combat tuberculosis, a better understanding of the pathophysiology of Mycobacterium tuberculosis is required. The Mycobacterium tuberculosis curli pili (MTP) adhesin, present on the surface of this pathogen, has previously been shown using functional genomics and global transcriptomics, to play an important role in establishing infection, bacterial aggregation, and modulating host response in vitro and in vivo.

Objective

This investigation aimed to determine the role of MTP in modulating the metabolism of M. tuberculosis, using mtp gene-knockout mutant and complemented strains.

Methods

Untargeted two-dimensional gas chromatography time-of-flight mass spectrometry, and bioinformatic analyses, were used to identify significant differences in the metabolite profiles among the wild-type, ∆mtp mutant and mtp-complemented strains, and validated with results generated by real-time quantitative PCR.

Results

A total of 28 metabolites were found to be significantly altered when comparing the ∆mtp mutant and the wild-type strains indicating a decreased utilisation of metabolites in cell wall biogenesis, a reduced efficiency in the breakdown of fatty acids, and decreased amino acid biosynthesis in the former strain. Comparison of the wild-type to mtp-complement, and ∆mtp to mtp-complemented strains revealed 10 and 16 metabolite differences, respectively. Real-time quantitative PCR results supported the metabolomics findings. Complementation of the ∆mtp mutant resulted in a partial restoration of MTP function.

Conclusion

The lack of the MTP adhesin resulted in various bacterial cell wall alterations and related metabolic changes. This study highlights the importance of MTP as a virulence factor and further substantiates its potential use as a suitable biomarker for the development of diagnostic tools and intervention therapeutics against TB.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available due to collaborative purposes and future publications but are available from the corresponding author on reasonable request. KEGG database reported in this study is accessible via [https://www.genome.jp/kegg/].

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Funding

This study was funded by MP’s South African National Research Foundation CPRR grant 105841 Grantholder-linked bursary and project running costs, and a University of KwaZulu-Natal College of Health Sciences scholarship.

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MP conceptualized and funded the study. MP, BP and DTL designed the study. SA and KSR contributed equally to the study, conducted experiments, analysed the data and drafted the manuscript. DB processed the samples and performed GCxGC-TOFMS. MVR conducted statistical bioinformatic analyses. SS provided RT-qPCR guidance and analytical support. All authors contributed to and approved the manuscript.

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Correspondence to M. Pillay.

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SA declares that she has no conflict of interest. KSR declares that she has no conflict of interest. SS declares he has no conflict of interest. DLT declares he has no conflict of interest. DB declares she has no conflict of interest. MVR declares she has no conflict of interest. BP declares he has no conflict of interest. MP declares she has no conflict of interest.

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The study was approved by the University of KwaZulu-Natal Biomedical Research Ethics Committee (BE254/17 and BE255/17).

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Ashokcoomar, S., Reedoy, K.S., Senzani, S. et al. Mycobacterium tuberculosis curli pili (MTP) deficiency is associated with alterations in cell wall biogenesis, fatty acid metabolism and amino acid synthesis. Metabolomics 16, 97 (2020). https://doi.org/10.1007/s11306-020-01720-z

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Keywords

  • M. tuberculosis curli pili
  • mtp
  • Adhesin
  • GC × GC-TOFMS
  • Metabolomics