Single nucleotide variation catalog from clinical isolates mapped on tertiary and quaternary structures of ESX-1-related proteins reveals critical regions as putative Mtb therapeutic targets

Tzfadia, O, Gijsbers, A, Vujkovic, A, Snobre, J, Vargas, R, Dewaele, K, Meehan, CJ ORCID: https://orcid.org/0000-0003-0724-8343, Farhat, M, Hakke, S, Peters, PJ, de Jong, BC, Siroy, A and Ravelli, RBG, 2024. Single nucleotide variation catalog from clinical isolates mapped on tertiary and quaternary structures of ESX-1-related proteins reveals critical regions as putative Mtb therapeutic targets. Microbiology Spectrum. ISSN 2165-0497

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Abstract

Proteins encoded by the ESX-1 genes of interest are essential for full virulence in all Mycobacterium tuberculosis complex (Mtbc) lineages, the pathogens causing the highest mortality worldwide. Identifying critical regions in these ESX-1-related proteins could provide preventive or therapeutic targets for Mtb infection, the game changer needed for tuberculosis control. We analyzed a compendium of whole genome sequences of clinical Mtb isolates from all lineages from >32,000 patients and identified single nucleotide polymorphisms. When mutations corresponding to all non-synonymous single nucleotide polymorphisms were mapped on structural models of the ESX-1 proteins, fully conserved regions emerged. Some could be assigned to known quaternary structures, whereas others could be predicted to be involved in yet-to-be-discovered interactions. Some mutants had clonally expanded (found in >1% of the isolates); these mutants were mostly located at the surface of globular domains, remote from known intra- and inter-molecular protein–protein interactions. Fully conserved intrinsically disordered regions of proteins were found, suggesting that these regions are crucial for the pathogenicity of the Mtbc. Altogether, our findings highlight fully conserved regions of proteins as attractive vaccine antigens and drug targets to control Mtb virulence. Extending this approach to the whole Mtb genome as well as other microorganisms will enhance vaccine development for various pathogens.

Item Type:	Journal article
Publication Title:	Microbiology Spectrum
Creators:	Tzfadia, O., Gijsbers, A., Vujkovic, A., Snobre, J., Vargas, R., Dewaele, K., Meehan, C.J., Farhat, M., Hakke, S., Peters, P.J., de Jong, B.C., Siroy, A. and Ravelli, R.B.G.
Publisher:	American Society for Microbiology
Date:	14 June 2024
ISSN:	2165-0497
Identifiers:	Number Type 10.1128/spectrum.03816-23 DOI 1907135 Other
Rights:	This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	26 Jun 2024 08:38
Last Modified:	26 Jun 2024 08:38
URI:	https://irep.ntu.ac.uk/id/eprint/51625

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