Systematic Discovery of Antibacterial and Antifungal Bacterial Toxins

Nachmias, Nimrod; Dotan, Noam; Shalom, Maor; Rivitz, Arbel; Shamash-Halevy, Naama; Oppenheimer-Shaanan, Yaara; Levy, Asaf

doi:10.1101/2021.10.19.465003

Cited by 4 publications

(4 citation statements)

References 108 publications

(183 reference statements)

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“…Also recently, new polymorfic toxin C-teminal domains (PTs) were described ( Nachmias et al ., 2022 ). The toxic domains of PT1 and PT7 were shown to be non-specific DNases that did not show sequence or structural similarity to any known nuclease ( Nachmias et al ., 2022 ). PT1 is likely secreted by the T6SS, while PT7 is probably secreted via the T7SS ( Nachmias et al ., 2022 ).…”

Section: Other Nuclease Domainsmentioning

confidence: 99%

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts

et al. 2023

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Bacteria live in polymicrobial communities and constantly compete for resources. These organisms have evolved an array of antibacterial weapons to inhibit the growth or kill competitors. The arsenal comprises antibiotics, bacteriocins, and contact-dependent effectors that are either secreted in the medium or directly translocated into target cells. During bacterial antagonistic encounters, several cellular components important for life become a weak spot prone to an attack. Nucleic acids and the machinery responsible for their synthesis are well conserved across the tree of life. These molecules are part of the information flow in the central dogma of molecular biology and mediate long- and short-term storage for genetic information. The aim of this review is to summarize the diversity of antibacterial molecules that target nucleic acids during antagonistic interbacterial encounters and discuss their potential to promote the emergence antibiotic resistance.

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Section: Other Nuclease Domainsmentioning

confidence: 99%

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts

et al. 2023

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“…We took advantage of the fact that Alphafold2 can not only predict accurate three-dimensional structures of monomers, but also of multimers 31,32,34,35,[49][50][51][52] . To establish a model of protein-protein interactions using Alphafold2, we used an external dataset of other toxin-immunity pairs derived from selected T6E pairs from SecReT6 database, toxin-antitoxin pairs from TADB database, and polymorphic toxin-immunity pairs identified by our laboratory [53][54][55][56] . We folded dimers of cognate toxin-immunity pairs, and as a control, we also folded randomized toxin-immunity pairs, i.e.…”

Section: Use Of Alphafold2 For Identification Of Predicted Toxin-immu...mentioning

confidence: 99%

“…The PAE score matrices in the intermolecular regions were flattened and concatenated into a simple array of PAE scores in that region. These distributions of PAE scores were retrieved from both cognate pairs of toxin-immunity proteins (from TADB, SecReT6, and PT-PIM [53][54][55][56] ) and from randomized pairings of these data into noncognate pairs (n = 333 total pairings). The means from the intermolecular PAE scores were used in a logistic regression model (implemented with sklearn.linear_model.LogisticRegression 102 , C = 0.25) to predict if the binding was "expected" (cognate pairs) or not expected (randomized pairs).…”

Section: Alphafold2mentioning

confidence: 99%

A genomic and structural bioinformatic pipeline identifies candidate type VI secretion antibacterial effector-immunity pairs

Geller

Zlotkin

Shalom

et al. 2023

Preprint

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Type VI secretion systems (T6SS) are common bacterial contractile injection systems that inject toxic "effector" proteins into neighboring cells. We bioinformatically investigated T6SS core proteins in 11,832 genomes of Gram negative bacteria. Comparison of T6SS core proteins that are covalently attached to toxic T6SS effector proteins (T6Es) versus those that are not revealed differences in phylogenetic distribution, physical properties, and genomic position. Using the data generated from our bioinformatic analysis, we developed a new genomic- and Alphafold2-based pipeline for discovery of putative T6Es. We experimentally validated the toxic and immunity activities of four putative antibacterial T6SS effector proteins and four cognate immunity genes from diverse species, respectively. We used Foldseek to predict possible mechanisms of action of the putative T6Es, which was much more effective than sequence-based methods. Evidence of the possible mechanisms of action of the putative T6Es was explored through fluorescence microscopy, where we observed cell wall-targeting, DNA degradation, and cell filamentation. This study shows how combining genomic data mining with new structure-based bioinformatic tools can facilitate identification of novel antibacterial toxins.

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“…The microbiology research community therefore lacks an integrated updated database that focuses on microbial toxins from various classes and their mapping to tens of thousands of microbial genomes. There are also recent reports that show that the same bacterial toxins can serve in one organism as part of self-inhibiting toxin-antitoxin modules, and in another organism, they evolved into toxin effectors that are being injected into target cells ( 5 , 27 , 28 ), and hence there is little benefit in separating toxins into different databases based on their specific biological function. Moreover, numerous toxin proteins are likely encoded in the tens of thousands of bacterial genomes, many of which are poorly studied non-model or non-pathogenic bacteria.…”

Section: Introductionmentioning

confidence: 99%

Toxinome—the bacterial protein toxin database

Danov,

Segev,

Bograd

et al. 2024

mBio

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Protein toxins are key molecular weapons in biology that are used to attack neighboring cells. Bacteria use protein toxins to kill or inhibit the growth of prokaryotic and eukaryotic cells using various modes of action that target essential cellular components. The toxins are responsible for shaping microbiomes in different habitats, for abortive phage infection, and for severe infectious diseases in animals and plants. Although several toxin databases have been developed, each one is devoted to a specific toxin family, and they encompass a relatively small number of toxins. Antimicrobial toxins are often accompanied by antitoxins (or immunity proteins) that neutralize the cognate toxins. Here, we combined toxins and antitoxins from many resources and created Toxinome, a comprehensive and updated bacterial protein toxin database. The Toxinome includes a total of 1,483,028 toxins and 491,345 antitoxins encoded in 59,475 bacterial genomes across the tree of life. We identified a depletion of toxin and antitoxin genes in bacteria that dwell in extreme temperatures. We defined 5,161 unique Toxin Islands within phylogenetically diverse bacterial genomes, which are loci dense in toxin and antitoxin genes. By focusing on the unannotated genes within these islands, we characterized a number of these genes as toxins or antitoxins. Finally, we developed an interactive Toxinome website ( http://toxinome.pythonanywhere.com ) that allows searching and downloading of our database. The Toxinome resource will be useful to the large research community interested in bacterial toxins and can guide toxin discovery and function elucidation, and infectious disease diagnosis and treatment. IMPORTANCE Microbes use protein toxins as important tools to attack neighboring cells, microbial or eukaryotic, and for self-killing when attacked by viruses. These toxins work through different mechanisms to inhibit cell growth or kill cells. Microbes also use antitoxin proteins to neutralize the toxin activities. Here, we developed a comprehensive database called Toxinome of nearly two million toxins and antitoxins that are encoded in 59,475 bacterial genomes. We described the distribution of bacterial toxins and identified that they are depleted by bacteria that live in hot and cold temperatures. We found 5,161 cases in which toxins and antitoxins are densely clustered in bacterial genomes and termed these areas “Toxin Islands.” The Toxinome database is a useful resource for anyone interested in toxin biology and evolution, and it can guide the discovery of new toxins.

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Systematic Discovery of Antibacterial and Antifungal Bacterial Toxins

Cited by 4 publications

References 108 publications

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts

Intercepting biological messages: Antibacterial molecules targeting nucleic acids during interbacterial conflicts

A genomic and structural bioinformatic pipeline identifies candidate type VI secretion antibacterial effector-immunity pairs

Toxinome—the bacterial protein toxin database

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