Exploiting bacterial DNA gyrase as a drug target: current state and perspectives.
TL;DR: Known gyrase-specific drugs and toxins are reviewed and the prospects for developing new antibacterials targeted to this enzyme are assessed.
Abstract: DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme.
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TL;DR: The molecules considered here might be used to treat biofilm-associated infections after significant structural modifications, thereby investigating its effective delivery in the host and minimum effective concentration must be capable of eradicating biofilm infections with maximum potency without posing any adverse side effects on the host.
Abstract: Biofilm refers to the complex, sessile communities of microbes found either attached to a surface or buried firmly in an extracellular matrix as aggregates. The biofilm matrix surrounding bacteria makes them tolerant to harsh conditions and resistant to antibacterial treatments. Moreover, the biofilms are responsible for causing a broad range of chronic diseases and due to the emergence of antibiotic resistance in bacteria it has really become difficult to treat them with efficacy. Furthermore, the antibiotics available till date are ineffective for treating these biofilm related infections due to their higher values of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), which may result in in-vivo toxicity. Hence, it is critically important to design or screen anti-biofilm molecules that can effectively minimize and eradicate biofilm related infections. In the present article, we have highlighted the mechanism of biofilm formation with reference to different models and various methods used for biofilm detection. A major focus has been put on various anti-biofilm molecules discovered or tested till date which may include herbal active compounds, chelating agents, peptide antibiotics, lantibiotics and synthetic chemical compounds along with their structures, mechanism of action and their respective MICs, MBCs, minimum biofilm inhibitory concentrations (MBICs) as well as the half maximal inhibitory concentration (IC50) values available in the literature so far. Different mode of action of anti biofilm molecules addressed here are inhibition via interference in the quorum sensing pathways, adhesion mechanism, disruption of extracellular DNA, protein, lipopolysaccharides, exopolysaccharides and secondary messengers involved in various signaling pathways. From this study, we conclude that the molecules considered here might be used to treat biofilm-associated infections after significant structural modifications, thereby investigating its effective delivery in the host. It should also be ensured that minimum effective concentration of these molecules must be capable of eradicating biofilm infections with maximum potency without posing any adverse side effects on the host.
754 citations
TL;DR: Topoisomerases remain as important therapeutic targets of anticancer agents and a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs is suggested.
Abstract: Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase-drug-DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.
268 citations
TL;DR: Some of the antimicrobial compounds that are produced by bacteria isolated from the gut environment, with a special focus on bacteriocins are summarized and the potential therapeutic application of these compounds to maintain homeostasis in the gut and the biocontrol of pathogenic bacteria is evaluated.
Abstract: Bacteria, Archaea, Eukarya and viruses coexist in the human gut, and this coexistence is functionally balanced by symbiotic or antagonistic relationships. Antagonism is often characterized by the production of antimicrobials against other organisms occupying the same environmental niche. Indeed, close co-evolution in the gut has led to the development of specialized antimicrobials, which is attracting increased attention as these may serve as novel alternatives to antibiotics and thereby help to address the global problem of antimicrobial resistance. The gastrointestinal (GI) tract is especially suitable for finding novel antimicrobials due to the vast array of microbes that inhabit it, and a considerable number of antimicrobial producers of both wide and narrow spectrum have been described. In this review, we summarize some of the antimicrobial compounds that are produced by bacteria isolated from the gut environment, with a special focus on bacteriocins. We also evaluate the potential therapeutic application of these compounds to maintain homeostasis in the gut and the biocontrol of pathogenic bacteria.
165 citations
Cites background from "Exploiting bacterial DNA gyrase as ..."
...There is an increasing interest in studying the inhibition of topoisomerases and gyrases as targets for designing antimicrobials, and the study of microcin B17 can offer further insights into the structure and functional analysis of this antimicrobial target.(106) In vivo studies have already demonstrated their ability to control infections in infants(107) and cattle....
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TL;DR: A novel series of 4'-methyl-N(2)-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity is identified by implementing a two-step structure-based design procedure.
Abstract: Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4′-methyl-N2-phenyl-[4,5′-bithiazole]-2,2′-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography, confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97–Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable i...
140 citations
TL;DR: The formerly enigmatic YcaO superfamily (DUF181), has been found to catalyze a unique phosphorylation of a ribosomal peptide backbone amide upon attack by different nucleophiles.
Abstract: With advances in sequencing technology, uncharacterized proteins and domains of unknown function (DUFs) are rapidly accumulating in sequence databases and offer an opportunity to discover new protein chemistry and reaction mechanisms. The focus of this review, the formerly enigmatic YcaO superfamily (DUF181), has been found to catalyze a unique phosphorylation of a ribosomal peptide backbone amide upon attack by different nucleophiles. Established nucleophiles are the side chains of Cys, Ser, and Thr which gives rise to azoline/azole biosynthesis in ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products. However, much remains unknown about the potential for YcaO proteins to collaborate with other nucleophiles. Recent work suggests potential in forming thioamides, macroamidines, and possibly additional post-translational modifications. This review covers all knowledge through mid-2016 regarding the biosynthetic gene clusters (BGCs), natural products, functions, mechanisms,...
135 citations
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TL;DR: Surprisingly, despite little or no sequence homology, both type IA and type IIA topoisomerases from prokaryotes and the typeIIA enzymes from eukaryotes share structural folds that appear to reflect functional motifs within critical regions of the enzymes.
Abstract: ▪ Abstract DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. In addition, these enzymes fine-tune the steady-state level of DNA supercoiling both to facilitate protein interactions with the DNA and to prevent excessive supercoiling that is deleterious. In recent years, the crystal structures of a number of topoisomerase fragments, representing nearly all the known classes of enzymes, have been solved. These structures provide remarkable insights into the mechanisms of these enzymes and complement previous conclusions based on biochemical analyses. Surprisingly, despite little or no sequence homology, both type IA and type IIA topoisomerases from prokaryotes and the type IIA enzymes from eukaryotes share structural folds that appear to reflect functional motifs within critical regions of the enzymes. The type IB enzymes are structurally distinct from a...
2,513 citations
"Exploiting bacterial DNA gyrase as ..." refers background in this paper
...B in the case of gyrase, which associate to form an A2B2 complex in the active enzyme (Champoux 2001)....
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...…or yeast topo II, are large single-subunit enzymes (∼170 kDa) that are active as homodimers, prokaryotic enzymes, such as gyrase and its close relative topo IV, are composed of two subunits: A and B in the case of gyrase, which associate to form an A2B2 complex in the active enzyme (Champoux 2001)....
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TL;DR: The results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
2,420 citations
"Exploiting bacterial DNA gyrase as ..." refers background in this paper
...In bacteria, this is thought to involve chromosome fragmentation, the induction of the SOS response, and the production of reactive oxygen species (Drlica et al. 2009; Kohanski et al. 2010; Kohanski et al. 2007)....
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...A consequence of quinolone-stabilised gyrase (or topo IV) complexes on DNA is chromosome fragmentation and ultimately cell death via a pathway that may involve active oxygen species (Dwyer et al. 2007; Kohanski et al. 2010; Kohanski et al. 2007)....
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...This is because relatively low occupancy of an inhibitor bound to its target can lead to sufficient proteinstabilised breaks in DNA to initiate a cascade of events that ultimately result in cell death (Drlica et al. 2009; Kohanski et al. 2010; Kohanski et al. 2007)....
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...A consequence of quinolone-stabilised gyrase (or topo IV) complexes on DNA is chromosome fragmentation and ultimately cell death via a pathway that may involve active oxygen species (Dwyer et al. 2007; Kohanski et al. 2010; Kohanski et al. 2007)....
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TL;DR: The multilayered effects of drug–target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing are discussed.
Abstract: Antibiotic drug-target interactions, and their respective direct effects, are generally well characterized. By contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be complex as they involve many genetic and biochemical pathways. In this Review, we discuss the multilayered effects of drug-target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, could be exploited to create new antibacterial therapies.
1,796 citations
TL;DR: This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors and discusses the common mechanism of action ofTopoisomerase poisons by interfacial inhibition and trapping of topisomerase cleavage complexes.
1,587 citations
"Exploiting bacterial DNA gyrase as ..." refers background in this paper
...cancer chemotherapy (Pommier et al. 2010; Tse-Dinh 2007; Bradbury and Pucci 2008)....
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...Due to their essential nature and to their mechanisms of action (see below), topoisomerases have become key drug targets both for antibacterial and anticancer chemotherapy (Pommier et al. 2010; Tse-Dinh 2007; Bradbury and Pucci 2008)....
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TL;DR: Although resistance was low in wild-type strains, higher levels of quinolone resistance arose readily by mutation, suggesting that a multiresistance plasmid can speed the development and spread of resistance to these valuable antimicrobial agents.
1,081 citations
"Exploiting bacterial DNA gyrase as ..." refers background in this paper
...Qnr is an example and is involved in plasmid-mediated fluoroquinolone resistance, originally found in Klebsiella pneumoniae (Martinez-Martinez et al. 1998)....
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...pneumoniae (Martinez-Martinez et al. 1998)....
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