Proteogenomic Investigation of Strain Variation in Clinical Mycobacterium tuberculosis Isolates

Abstract

Mycobacterium tuberculosis consists of a large number of different strains that display unique virulence characteristics. Whole-genome sequencing has revealed substantial genetic diversity among clinical M. tuberculosis isolates, and elucidating the phenotypic variation encoded by this genetic diversity will be of the utmost importance to fully understand M. tuberculosis biology and pathogenicity. In this study, we integrated whole-genome sequencing and mass spectrometry (GeLC-MS/MS) to reveal strain-specific characteristics in the proteomes of two clinical M. tuberculosis Latin American-Mediterranean isolates. Using this approach, we identified 59 peptides containing single amino acid variants, which covered ∼9% of all coding nonsynonymous single nucleotide variants detected by whole-genome sequencing. Furthermore, we identified 29 distinct peptides that mapped to a hypothetical protein not present in the M. tuberculosis H37Rv reference proteome. Here, we provide evidence for the expression of this protein in the clinical M. tuberculosis SAWC3651 isolate. The strain-specific databases enabled confirmation of genomic differences (i.e., large genomic regions of difference and nonsynonymous single nucleotide variants) in these two clinical M. tuberculosis isolates and allowed strain differentiation at the proteome level. Our results contribute to the growing field of clinical microbial proteogenomics and can improve our understanding of phenotypic variation in clinical M. tuberculosis isolates.

The PRIDE database and related tools and resources in 2019: improving support for quantification data

“…Two popular applications are proteogenomics approaches (for human and the main model organisms, e.g. (33,34)), and the discovery of novel PTMs (Post-Translational Modifications). Recent reviews in re-use of public proteomics data are available (32,35).…”

Comprehensive Characterization of the Attenuated Double Auxotroph Mycobacterium tuberculosisΔleuDΔpanCD as an Alternative to H37Rv

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Benzofuroxan Derivatives as Potent Agents against Multidrug‐Resistant Mycobacterium tuberculosis

“…[64] Both in vitro and in vivo, the differences in the profile of pathogenicity and virulence are important factors and, therefore, it is recommended to use different strains for a study to ensure reliable results and accurate prediction of the effect of the compound in a population. [64][65][66] In the present study, compounds 5 b (Lapdesf-20-5b) and 5 n (Lapdesf-20-5n) were identified as the most potent against the resistant strains and, therefore, the most promising. These compounds demonstrated potent activity against all the evaluated strains.…”