Gene evolutionary trajectories in
            <i>Mycobacterium tuberculosis</i>
            reveal temporal signs of selection

Chiner‐Oms, Álvaro; López, Mariana G.; Moreno-Molina, Miguel; Furió, Victoria; Comas, Iñaki

doi:10.1073/pnas.2113600119

Cited by 20 publications

(21 citation statements)

References 82 publications

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“…The dN/dS of resR was higher in drug-resistant strains compared with drug-sensitive strains (Fig. 1D), suggesting that resR mutations are associated with the evolution of drug resistance and consistent with a recent study showing that resR mutations were associated with a multidrug-resistant tuberculosis (TB) phenotype (8). Protein structural modeling indicated that most resR clinical mutations occur in the merR-type helix-turnhelix DNA-binding domain, with the most common mutations located at the interface between ResR and duplex DNA (Fig.…”

Section: Ongoing Positive Selection In the Mtb Populationsupporting

confidence: 91%

Tuberculosis treatment failure associated with evolution of antibiotic resilience

Liu

Zhu

Dulberger

et al. 2022

Science

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The widespread use of antibiotics has placed bacterial pathogens under intense pressure to evolve new survival mechanisms. Genomic analysis of 51,229 Mycobacterium tuberculosis ( Mtb ) clinical isolates has identified an essential transcriptional regulator, Rv1830 , herein called resR for resilience regulator, as a frequent target of positive (adaptive) selection. resR mutants do not show canonical drug resistance or drug tolerance but instead shorten the post-antibiotic effect, meaning that they enable Mtb to resume growth after drug exposure substantially faster than wild-type strains. We refer to this phenotype as antibiotic resilience. ResR acts in a regulatory cascade with other transcription factors controlling cell growth and division, which are also under positive selection in clinical isolates of Mtb . Mutations of these genes are associated with treatment failure and the acquisition of canonical drug resistance.

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Section: Ongoing Positive Selection In the Mtb Populationsupporting

confidence: 91%

Tuberculosis treatment failure associated with evolution of antibiotic resilience

Liu

Zhu

Dulberger

et al. 2022

Science

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“…The movement or conservation of genes in bacteria is a fundamental factor related to virulence, survival, and host adaptability, allowing them to co-evolve together [ 55 ]. Several studies in M. tuberculosis have shown that the ability of transmission within populations, latency periods, and drug resistance are due to genetic differences within the members of the M. tuberculosis complex and that many of its genes have been under positive selection at different periods [ 56 ]. Furthermore, the composition within its genome remains relatively stable due to the absence of horizontal gene transfer, and this superficial level of genetic variation is probably because these pathogens have a strongly clonal nature [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative genomics of drug-resistant strains of Mycobacterium tuberculosis in Ecuador

et al. 2022

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Background Tuberculosis is a serious infectious disease affecting millions of people. In spite of efforts to reduce the disease, increasing antibiotic resistance has contributed to persist in the top 10 causes of death worldwide. In fact, the increased cases of multi (MDR) and extreme drug resistance (XDR) worldwide remains the main challenge for tuberculosis control. Whole genome sequencing is a powerful tool for predicting drug resistance-related variants, studying lineages, tracking transmission, and defining outbreaks. This study presents the identification and characterization of resistant clinical isolates of Mycobacterium tuberculosis including a phylogenetic and molecular resistance profile study by sequencing the complete genome of 24 strains from different provinces of Ecuador. Results Genomic sequencing was used to identify the variants causing resistance. A total of 15/21 isolates were identified as MDR, 4/21 as pre-XDR and 2/21 as XDR, with three isolates discarded due to low quality; the main sub-lineage was LAM (61.9%) and Haarlem (19%) but clades X, T and S were identified. Of the six pre-XDR and XDR strains, it is noteworthy that five come from females; four come from the LAM sub-lineage and two correspond to the X-class sub-lineage. A core genome of 3,750 genes, distributed in 295 subsystems, was determined. Among these, 64 proteins related to virulence and implicated in the pathogenicity of M. tuberculosis and 66 possible pharmacological targets stand out. Most variants result in nonsynonymous amino acid changes and the most frequent genotypes were identified as conferring resistance to rifampicin, isoniazid, ethambutol, para-aminosalicylic acid and streptomycin. However, an increase in the resistance to fluoroquinolones was detected. Conclusion This work shows for the first time the variability of circulating resistant strains between men and women in Ecuador, highlighting the usefulness of genomic sequencing for the identification of emerging resistance. In this regard, we found an increase in fluoroquinolone resistance. Further sampling effort is needed to determine the total variability and associations with the metadata obtained to generate better health policies.

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“…Filtered reads were mapped with bwa [43] to a predicted MTBC ancestor reference sequence [44] using default parameters, and then processed using the SAMtools [45] and Picard [46] programs. Variant calling was performed with VarScan [47] following published parameters [48]. Once variants had been obtained, we used a mapping filter to discard variants present in repetitive genomic regions such as in PE/PPE gene families or phages [5].…”

Section: Methodsmentioning

confidence: 99%

Lack of methoxy-mycolates characterizes the geographically restricted lineage 7 of Mycobacterium tuberculosis complex

et al. 2023

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Lineage 7 (L7) emerged in the phylogeny of the Mycobacterium tuberculosis complex (MTBC) subsequent to the branching of ‘ancient’ lineage 1 and prior to the Eurasian dispersal of ‘modern’ lineages 2, 3 and 4. In contrast to the major MTBC lineages, the current epidemiology suggests that prevalence of L7 is highly confined to the Ethiopian population, or when identified outside of Ethiopia, it has mainly been in patients of Ethiopian origin. To search for microbiological factors that may contribute to its restricted distribution, we compared the genome of L7 to the genomes of globally dispersed MTBC lineages. The frequency of predicted functional mutations in L7 was similar to that documented in other lineages. These include mutations characteristic of modern lineages – such as constitutive expression of nitrate reductase – as well as mutations in the VirS locus that are commonly found in ancient lineages. We also identified and characterized multiple lineage-specific mutations in L7 in biosynthesis pathways of cell wall lipids, including confirmed deficiency of methoxy-mycolic acids due to a stop-gain mutation in the mmaA3 gene that encodes a methoxy-mycolic acid synthase. We show that the abolished biosynthesis of methoxy-mycolates of L7 alters the cell structure and colony morphology on selected growth media and impacts biofilm formation. The loss of these mycolic acid moieties may change the host–pathogen dynamic for L7 isolates, explaining the limited geographical distribution of L7 and contributing to further understanding the spread of MTBC lineages across the globe.

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Gene evolutionary trajectories in Mycobacterium tuberculosis reveal temporal signs of selection

Cited by 20 publications

References 82 publications

Tuberculosis treatment failure associated with evolution of antibiotic resilience

Tuberculosis treatment failure associated with evolution of antibiotic resilience

Comparative genomics of drug-resistant strains of Mycobacterium tuberculosis in Ecuador

Lack of methoxy-mycolates characterizes the geographically restricted lineage 7 of Mycobacterium tuberculosis complex

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