Mycobacterium tuberculosis Rv0366c-Rv0367c encodes a non-canonical PezAT-like toxin-antitoxin pair

Tandon, Himani; Sharma, Arun; Sandhya, Sankaran; Singh, Ramandeep

doi:10.1038/s41598-018-37473-y

Cited by 13 publications

(19 citation statements)

References 60 publications

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“…In agreement, we also observed that overexpression of VapC21 led to an increase in amikacin-tolerant and ethambutol-tolerant persisters in M. smegmatis. Although, the contribution of Type II TA systems in bacterial persistence and drug tolerance are controversial, our results are in agreement with other studies, where overexpression of Type II toxins is associated with increased tolerance of E. coli, M. smegmatis or M. tuberculosis upon exposure to various drugs (Keren et al, 2004;Dorr et al, 2010;Singh et al, 2010;Holden and Errington, 2018;Ronneau and Helaine, 2019;Tandon et al, 2019a).…”

Section: Discussionsupporting

confidence: 92%

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

et al. 2020

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The prokaryotic ubiquitous Toxin-antitoxin (TA) modules encodes for a stable toxin and an unstable antitoxin. VapBC subfamily is the most abundant Type II TA system in M. tuberculosis genome. However, the exact physiological role for most of these Type II TA systems are still unknown. Here, we have comprehensively characterized the VapBC21 TA locus from M. tuberculosis. The overexpression of VapC21 inhibited mycobacterial growth in a bacteriostatic manner and as expected, growth inhibition was abrogated upon co-expression of the cognate antitoxin, VapB21. We observed that the deletion of vapC21 had no noticeable influence on the in vitro and in vivo growth of M. tuberculosis. Using co-expression and biophysical studies, we observed that in addition to VapB21, VapC21 is also able to interact with non-cognate antitoxin, VapB32. The strength of interaction varied between the cognate and non-cognate TA pairs. The overexpression of VapC21 resulted in differential expression of approximately 435 transcripts in M. tuberculosis. The transcriptional profiles obtained upon ectopic expression of VapC21 was similar to those reported in M. tuberculosis upon exposure to stress conditions such as nutrient starvation and enduring hypoxic response. Further, VapC21 overexpression also led to increased expression of WhiB7 regulon and bacterial tolerance to aminoglycosides and ethambutol. Taken together, these results indicate that a complex network of interactions exists between non-cognate TA pairs and VapC21 contributes to drug tolerance in vitro.

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Section: Discussionsupporting

confidence: 92%

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

et al. 2020

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“…In contrast, most other toxins studied in Mtb exert a bacteriostatic effect (Singh et al, 2010;Tiwari et al, 2015;Agarwal et al, 2018;Sharrock et al, 2018;Tandon et al, 2019). This suggests that, among…”

Section: Discussionmentioning

confidence: 98%

“…Activation of DarT Mtb has a bactericidal effect (Figure 3b), similar to induction of MbcT, the toxin of the only other characterized TA system in Mtb harboring an essential antitoxin (Freire et al ., 2019). In contrast, most other toxins studied in Mtb exert a bacteriostatic effect (Singh et al ., 2010; Tiwari et al ., 2015; Agarwal et al ., 2018; Sharrock et al ., 2018; Tandon et al ., 2019). This suggests that, among TA systems, DarG Mtb may be an attractive drug target.…”

Section: Discussionmentioning

confidence: 99%

Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA‐damage response and leads to cell death

Zaveri

Wang

Botella

et al. 2020

Molecular Microbiology

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Toxin-antitoxin (TA) systems are ubiquitously present in prokaryotic genomes and consist of a toxic protein that inhibits an essential cellular process and a counteracting antitoxin that binds to and neutralizes the toxin (Yamaguchi et al., 2011). TA systems were originally discovered due to their ability to prevent plasmid loss by post-segregational killing (Ogura and Hiraga, 1983; Gerdes et al., 1986). They have subsequently been implicated in various cellular pathways including phage defense, genome stabilization, and bacterial per

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“…The in silico analysis of strain GM12 revealed 18 chromosomally encoded putative candidate TAS elements of which five candidate TAS with the lowest TASmania output e-values were short-listed for our study. In Mycobacterium tuberculosis, a deathly human respiratory pathogen with a much larger genome, at least 79 TAS have been reported to be involved in numerous mechanisms regarding cellular processes such as cell death, persistence and virulence [29][30][31]. In contrast, Campylobacter jejuni, a human pathogen causing diarrhea, has been reported to contain no more than three TAS, which underlines a great variety in the abundance of TAS in different prokaryotic genera [29].…”

Section: Discussionmentioning

confidence: 99%

Minimalistic mycoplasmas harbor different functional toxin-antitoxin systems

Hill

Akarsu

Barbarroja

et al. 2021

Preprint

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Mycoplasmas are minute bacteria controlled by very small genomes ranging from 0.6 to 1.4 Mbp. They lack a cell wall and have been suggested to have progressed through reductive evolution from phylogenetically closely related Clostridia. They are known to colonize the respiratory tract or the urogenital tract among other organs and can cause chronic and subclinical diseases associated with long persistence of the causative agent. Toxin-antitoxin systems (TAS) are genetic elements that have been described for several respiratory and urogenital pathogens as well as for Clostridia, but never for pathogenic mycoplasmas. Here we describe for the first-time different types of TAS in a Mycoplasma pathogen, namely M. mycoides subsp. capri. We identified candidate TAS in silico via TASmania database. Two candidate TAS identified in silico and another candidate TAS suggested in a minimal cell based on transposon mutagenesis were systematically tested for their functionality in hosts with different phylogenetic distance using heterologous expression. Phylogenetic distance of the host used for heterologous expression influenced the outcome of the functional testing. We corroborated functionality of the three candidate TAS in Mycoplasma capricolum subsp. capricolum. Moreover, we confirmed transcription and translation of molecules of the TAS investigated during in vitro growth. We sequence analyzed 15 genomes of M. mycoides subsp. capri and revealed an unequal distribution of the TAS studied pointing towards dynamic gain and loss of TAS within the species.Author summaryMycoplasmas have a minimal genome and have never been shown to possess TAS. In this work we showed the presence of different functional TAS systems in Mycoplasma mycoides subsp. capri, a caprine pathogen for the first time. Sequence analysis of a number of Mycoplasma mycoides subsp. capri strains revealed a plasticity of the genome with respect to TAS carriage. This work paves the way to investigate the biological role of TAS (e.g. persistence, stress tolerance) during infection using mycoplasmas as a simple model organism. Since most mycoplasmas lack classical virulence factors such as exotoxins and go into a kind of stealth mode to evade the immune system, TAS are likely to contribute to the parasitic lifestyle of mycoplasmas and should be investigated in that respect. The availability of synthetic genomics tools to modify a range of Mycoplasma pathogens and well-established challenge models for the latter mycoplasmas will foster future research on TAS in mycoplasmas.

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Mycobacterium tuberculosis Rv0366c-Rv0367c encodes a non-canonical PezAT-like toxin-antitoxin pair

Cited by 13 publications

References 60 publications

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the DNA‐damage response and leads to cell death

Minimalistic mycoplasmas harbor different functional toxin-antitoxin systems

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