One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan, Wai Ting; Balsa, Dolors; Espinosa, Manuel

doi:10.1093/femsre/fuv002

Cited by 70 publications

(100 citation statements)

References 185 publications

(226 reference statements)

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“…TA systems have recently received much attention as one of the most promising antibacterial targets [90,182,183,184,185] because they are widely distributed in almost all of the most important bacterial pathogens but not in eukaryotic cells. One of the powerful antibacterial strategies is an artificial activation of the toxin, which could be accomplished by using small compounds or peptides as inhibitors of the protein (toxin)-protein (antitoxin) interactions (Figure 9A).…”

Section: Exploitation Of Ta Systems For the Development Of Novel Amentioning

confidence: 99%

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

Lee

2016

Toxins

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Bacterial toxin–antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein–protein interactions. Accumulating knowledge about the structure–function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems.

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Section: Exploitation Of Ta Systems For the Development Of Novel Amentioning

confidence: 99%

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

Lee

2016

Toxins

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“…Thus, the so-called mobilome (4) participates in the spread of antibiotic resistance, which is expected to cause 10 million casualties annually by 2050, and the consequent huge economic burden (amr-review.org/sites/default/files/Report-52.15.pdf). This has generated a unanimous call for new approaches to deal with infectious diseases caused by pathogenic bacteria (5).…”

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confidence: 99%

Structural basis of a histidine-DNA nicking/joining mechanism for gene transfer and promiscuous spread of antibiotic resistance

Pluta

Boer

Lorenzo-Díaz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Relaxases are metal-dependent nucleases that break and join DNA for the initiation and completion of conjugative bacterial gene transfer. Conjugation is the main process through which antibiotic resistance spreads among bacteria, with multidrug-resistant staphylococci and streptococci infections posing major threats to human health. The MOB V family of relaxases accounts for approximately 85% of all relaxases found in Staphylococcus aureus isolates. Here, we present six structures of the MOB V relaxase MobM from the promiscuous plasmid pMV158 in complex with several origin of transfer DNA fragments. A combined structural, biochemical, and computational approach reveals that MobM follows a previously uncharacterized histidine/metal-dependent DNA processing mechanism, which involves the formation of a covalent phosphoramidate histidine-DNA adduct for cell-to-cell transfer. We discuss how the chemical features of the high-energy phosphorus-nitrogen bond shape the dominant position of MOB V histidine relaxases among small promiscuous plasmids and their preference toward Gram-positive bacteria.histidine relaxase | antibiotic resistance | horizontal gene transfer | X-ray structure | Staphylococcus aureus A cquisition of exogenous genetic material by bacteria is achieved via conjugative DNA transfer of mobile genetic elements, such as plasmids and especially integrative and conjugative elements and integrative and mobilizable elements (1). Such processes of horizontal gene transfer (HGT) are considered a strong driving force in bacterial evolution and in the ability of bacteria to colonize different niches (2). In addition to permitting the rapid evolution of the bacterial pangenome, HGT is involved in the acquisition of genetic traits that may confer selective advantages to the recipient bacteria, including antibiotic resistance (3). This is particularly important when resistance genes encoded by mobile elements are spread explosively among bacteria in hospitals, posing a serious threat to public health systems (www.cdc.gov/drugresistance/threat-report-2013; www. who.int/drugresistance/documents/surveillancereport/en/). Thus, the so-called mobilome (4) participates in the spread of antibiotic resistance, which is expected to cause 10 million casualties annually by 2050, and the consequent huge economic burden (amr-review.org/sites/default/files/Report-52.15.pdf). This has generated a unanimous call for new approaches to deal with infectious diseases caused by pathogenic bacteria (5).A main performer in HGT is the protein relaxase, a topoisomeraselike enzyme that cleaves supercoiled plasmid DNA in a strandand sequence-specific manner and ligates it after cell-to-cell transfer. Relaxases start DNA transfer by conjugation on recognition of their target DNA, the origin of transfer (oriT), on which they mediate generation of a hairpin-loop structure that leaves the dinucleotide to be cleaved (the nic site) in a singlestranded (ss) DNA configuration (Fig. 1B) (6, 7). On the oriT, the relaxase assembles with other proteins p...

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“…Type II TA systems have attracted interest as targets for the development of inhibitors that would prevent binding, thereby freeing the toxin to halt cell growth (36,49). Since models based on crystal structures show that VapB C-terminal domains make extensive contacts with their cognate toxin, the possibility that small molecules could inhibit TA interactions seems limited (7,37,38,40,41).…”

Section: Discussionmentioning

confidence: 99%

Structural Determinants for Antitoxin Identity and Insulation of Cross Talk between Homologous Toxin-Antitoxin Systems

Walling

Butler

2016

J Bacteriol

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Toxin-antitoxin (TA) systems are ubiquitous in bacteria and archaea, where they play a pivotal role in the establishment and maintenance of dormancy. Under normal growth conditions, the antitoxin neutralizes the toxin. However, under conditions of stress, such as nutrient starvation or antibiotic treatment, cellular proteases degrade the antitoxin, and the toxin functions to arrest bacterial growth. We characterized the specificity determinants of the interactions between VapB antitoxins and VapC toxins from nontypeable Haemophilus influenzae (NTHi) in an effort to gain a better understanding of how antitoxins control toxin activity and bacterial persistence. We studied truncated and full-length antitoxins with single amino acid mutations in the toxin-binding domain. Coexpressing the toxin and antitoxin in Escherichia coli and measuring bacterial growth by dilution plating assayed the ability of the mutant antitoxins to neutralize the toxin. Our results identified two single amino acid residues (W48 and F52) in the C-terminal region of the VapB2 antitoxin necessary for its ability to neutralize its cognate VapC2 toxin. Additionally, we attempted to alter the specificity of VapB1 by making a mutation that would allow it to neutralize its noncognate toxin. A mutation in VapB1 to contain the tryptophan residue identified herein as important in the VapB2-VapC2 interaction resulted in a VapB1 mutant (the T47W mutant) that binds to and neutralizes both its cognate VapC1 and noncognate VapC2 toxins. This represents the first example of a single mutation causing relaxed specificity in a type II antitoxin. IMPORTANCEToxin-antitoxin systems are of particular concern in pathogenic organisms, such as nontypeable Haemophilus influenzae, as they can elicit dormancy and persistence, leading to chronic infections and failure of antibiotic treatment. Despite the importance of the TA interaction, the specificity determinants for VapB-VapC complex formation remain uncharacterized. Thus, our understanding of how antitoxins control toxin-induced dormancy and bacterial persistence requires thorough investigation of antitoxin specificity for its cognate toxin. This study characterizes the crucial residues of the VapB2 antitoxin from NTHi necessary for its interaction with VapC2 and provides the first example of a single amino acid change altering the toxin specificity of an antitoxin.T oxin-antitoxin (TA) systems are ubiquitous in bacteria and archaea, where they play a pivotal role in the establishment and maintenance of dormancy. Originally discovered as addictive elements involved in postsegregational killing during cell division, they have since been identified as playing a critical role in responding to stress (1-3). TA systems are typically encoded by a single operon that produces a stable protein toxin and its cognate labile antitoxin, with the gene encoding the antitoxin located upstream of the toxin in most cases (4). Under normal growth conditions, the antitoxin, which may be a protein (types II, IV, and V) or an RNA...

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One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Cited by 70 publications

References 185 publications

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

Structural basis of a histidine-DNA nicking/joining mechanism for gene transfer and promiscuous spread of antibiotic resistance

Structural Determinants for Antitoxin Identity and Insulation of Cross Talk between Homologous Toxin-Antitoxin Systems

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