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Biomedicine & Pharmacotherapy =... Jul 2018DNA gyrase is classified as topoisomerase II, an ATP-dependent enzyme that is vital in the transcription, replication of DNA and chromosome segregation processes. It... (Review)
Review
DNA gyrase is classified as topoisomerase II, an ATP-dependent enzyme that is vital in the transcription, replication of DNA and chromosome segregation processes. It plays a crucial role in all bacteria except higher eukaryotes and this makes it a desirable and viable therapeutic target for development of new antibacterial agents. Fluoroquinolones are commonly used effective antibacterial agents that target DNA gyrase, however the spectrum of side-effects and emerging bacterial resistance with no new drugs in the antibacterial pipeline has fuelled intensive research in this area. New chemical entities with varied scaffolds possessing DNA gyrase inhibiting properties have been determined by screening chemical libraries that could serve as good leads for antibacterial drug development. A wide range of natural products and protein-based compounds have been identified and studied as DNA gyrase inhibitors and this adds a huge amount of structural diversity that can be exploited and harnessed in the discovery of new antibacterial agents. The development of new chemical compounds with DNA gyrase inhibitory activity (from natural sources, random screens or rational design) will further validate/corroborate the potential of this enzyme as a useful target. This review presents an overview of the DNA gyrase inhibitors obtained from natural and synthetic sources, their syntheses schemes and spectrum of biological activity of a variety of scaffolds and their analogues. The authors hope to provide focused direction for development of new chemical entities, synthetic routes for analogue synthesis, structure activity relationships and biological activity. The most potent ones can be used as templates to design novel compounds targeting DNA gyrase and are effective against resistant bacterial strains and biofilms.
Topics: Anti-Bacterial Agents; DNA Gyrase; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Topoisomerase II Inhibitors
PubMed: 29710509
DOI: 10.1016/j.biopha.2018.04.021 -
European Journal of Medicinal Chemistry Aug 2020Antimicrobial resistance is one of the greatest challenges facing the world today. In the United States alone, it is responsible for the death of more than 20,000 people... (Review)
Review
Antimicrobial resistance is one of the greatest challenges facing the world today. In the United States alone, it is responsible for the death of more than 20,000 people each year. DNA gyrase, a well-validated drug target, is involved in bacterial DNA replication, repair and decatenation. Currently, the fluoroquinolone class of antibacterials act via inhibition of the DNA gyrase enzyme. However, their efficacy is hindered by the increasing incidence of antimicrobial resistance. Therefore, in this review, we provide an account regarding the structure of DNA gyrase and quinoline and non-quinolone inhibitors published within the last five years (2015-2019). Further, we also discuss molecular interactions and structure-activity relationship studies of the published inhibitors.
Topics: Anti-Bacterial Agents; Bacteria; DNA Gyrase; Microbial Sensitivity Tests; Molecular Structure; Topoisomerase II Inhibitors
PubMed: 32460040
DOI: 10.1016/j.ejmech.2020.112326 -
Current Topics in Medicinal Chemistry 2019DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolone class of antibacterials. However, owing to increasing drug resistance as... (Review)
Review
DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolone class of antibacterials. However, owing to increasing drug resistance as well as a concomitant reduction in the availability of newer classes of antibiotics, fluoroquinolones are increasingly being over-utilized in order to treat serious infections, including multi-drug resistant tuberculosis. This, in turn, increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in gyrA, leading to class-wide resistance. In this review, we provide an overview of the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and development status.
Topics: Antitubercular Agents; DNA Gyrase; Drug Discovery; Drug Resistance, Multiple, Bacterial; Humans; Molecular Structure; Mycobacterium tuberculosis; Topoisomerase II Inhibitors; Tuberculosis
PubMed: 30834837
DOI: 10.2174/1568026619666190304130218 -
Briefings in Functional Genomics Apr 2023Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in... (Review)
Review
Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in the appearance of multiple drug resistance in bacterial pathogens and a decline in the discovery of novel antibiotics. DNA gyrase is an attractive target used for antibiotic discovery due to its vital role in bacterial DNA replication and segregation in addition to its absence in mammalian organisms. Despite the presence of successful antibiotics targeting this enzyme, there is a need to bypass the resistance against this validated drug target. Hence, drug development in DNA gyrase is a highly active research area. In addition to the conventional binding sites for the novobiocin and fluoroquinolone antibiotics, several novel sites are being exploited for drug discovery. The binding sites for novel bacterial type II topoisomerase inhibitor (NBTI), simocyclinone, YacG, Thiophene and CcdB are structurally and biochemically validated active sites, which inhibit the supercoiling activity of topoisomerases. The novel chemical moieties with varied scaffolds have been identified to target DNA gyrase. Amongst them, the NBTI constitutes the most advanced DNA gyrase inhibitor which are in phase III trial of drug development. The present review aims to classify the novel binding sites other than the conventional novobiocin and quinolone binding pocket to bypass the resistance due to mutations in the DNA gyrase enzyme. These sites can be exploited for the identification of new scaffolds for the development of novel antibacterial compounds.
Topics: Animals; DNA Gyrase; Novobiocin; Anti-Bacterial Agents; Topoisomerase II Inhibitors; Mammals
PubMed: 36064602
DOI: 10.1093/bfgp/elac029 -
International Journal of Molecular... May 2018Gyrase is a type IIA topoisomerase that catalyzes negative supercoiling of DNA. The enzyme consists of two GyrA and two GyrB subunits. It is believed to introduce... (Review)
Review
Gyrase is a type IIA topoisomerase that catalyzes negative supercoiling of DNA. The enzyme consists of two GyrA and two GyrB subunits. It is believed to introduce negative supercoils into DNA by converting a positive DNA node into a negative node through strand passage: First, it cleaves both DNA strands of a double-stranded DNA, termed the G-segment, and then it passes a second segment of the same DNA molecule, termed the T-segment, through the gap created. As a two-fold symmetric enzyme, gyrase contains two copies of all elements that are key for the supercoiling reaction: The GyrB subunits provide two active sites for ATP binding and hydrolysis. The GyrA subunits contain two C-terminal domains (CTDs) for DNA binding and wrapping to stabilize the positive DNA node, and two catalytic tyrosines for DNA cleavage. While the presence of two catalytic tyrosines has been ascribed to the necessity of cleaving both strands of the G-segment to enable strand passage, the role of the two ATP hydrolysis events and of the two CTDs has been less clear. This review summarizes recent results on the role of these duplicate elements for individual steps of the supercoiling reaction, and discusses the implications for the mechanism of DNA supercoiling.
Topics: Animals; DNA; DNA Gyrase; DNA Topoisomerases, Type II; Humans; Nucleic Acid Conformation; Protein Subunits; Structure-Activity Relationship
PubMed: 29772727
DOI: 10.3390/ijms19051489 -
EcoSal Plus 2015DNA topoisomerases are enzymes that control the topology of DNA in all cells. There are two types, I and II, classified according to whether they make transient single-... (Review)
Review
DNA topoisomerases are enzymes that control the topology of DNA in all cells. There are two types, I and II, classified according to whether they make transient single- or double-stranded breaks in DNA. Their reactions generally involve the passage of a single- or double-strand segment of DNA through this transient break, stabilized by DNA-protein covalent bonds. All topoisomerases can relax DNA, but DNA gyrase, present in all bacteria, can also introduce supercoils into DNA. Because of their essentiality in all cells and the fact that their reactions proceed via DNA breaks, topoisomerases have become important drug targets; the bacterial enzymes are key targets for antibacterial agents. This article discusses the structure and mechanism of topoisomerases and their roles in the bacterial cell. Targeting of the bacterial topoisomerases by inhibitors, including antibiotics in clinical use, is also discussed.
Topics: Anti-Bacterial Agents; Bacteria; Bacteriocins; DNA Gyrase; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA, Bacterial; DNA, Superhelical; Models, Molecular; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors
PubMed: 26435256
DOI: 10.1128/ecosalplus.ESP-0010-2014 -
Future Medicinal Chemistry May 2018New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in... (Review)
Review
New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topology during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular reference to Gram-negative bacteria.
Topics: Amides; Anti-Bacterial Agents; Binding, Competitive; DNA Gyrase; Drug Discovery; Gram-Negative Bacteria; Mycobacterium tuberculosis; Topoisomerase II Inhibitors
PubMed: 29787300
DOI: 10.4155/fmc-2017-0257 -
DNA Repair Apr 2014DNA topoisomerases inter-convert different DNA topoisomers in the cell. They catalyze the introduction or relaxation of DNA supercoils, as well as catenation and... (Review)
Review
DNA topoisomerases inter-convert different DNA topoisomers in the cell. They catalyze the introduction or relaxation of DNA supercoils, as well as catenation and decatenation. Members of the type I topoisomerase family cleave a single strand of their double-stranded DNA substrate, whereas enzymes of the type II family cleave both DNA strands. Bacterial DNA gyrase, a type II topoisomerase, catalyzes the introduction of negative supercoils into DNA in an ATP-dependent reaction. Gyrase is not present in humans, and constitutes an attractive drug target for the treatment of bacterial and parasite infections. DNA supercoiling by gyrase is believed to occur by a strand passage mechanism, in which one segment of the double-stranded DNA substrate is passed through a (transient) break in a second segment. This mechanism requires the coordinated opening and closing of three protein interfaces, so-called gates, to ensure the directionality of strand passage toward negative supercoiling. Single molecule fluorescence resonance energy transfer experiments are ideally suited to investigate conformational changes during the catalytic cycle of DNA topoisomerases. In this review, we summarize the current knowledge on the cascade of DNA- and nucleotide-induced conformational changes in gyrase that lead to strand passage and negative supercoiling of DNA. We discuss how these conformational changes couple ATP hydrolysis to DNA supercoiling in gyrase, and how the common mechanistic principle of coordinated gate opening and closing is modulated to allow for the catalysis of different reactions by different type II topoisomerases.
Topics: Bacteria; Binding Sites; DNA Gyrase; DNA Topoisomerase IV; DNA, Bacterial; DNA, Superhelical; Models, Molecular; Nucleic Acid Conformation; Protein Conformation; Protein Structure, Tertiary
PubMed: 24674625
DOI: 10.1016/j.dnarep.2014.01.011 -
Methods in Molecular Biology (Clifton,... 2018Most bacterial cells have a motor enzyme termed DNA gyrase, which is a type-2 topoisomerase that reduces the linking number (Lk) of DNA. The supercoiling energy...
Most bacterial cells have a motor enzyme termed DNA gyrase, which is a type-2 topoisomerase that reduces the linking number (Lk) of DNA. The supercoiling energy generated by gyrase is essential to maintain the bacterial chromosome architecture and regulate its DNA transactions. This chapter describes the use of agarose-gel electrophoresis to detect the unconstrained supercoiling of DNA generated by gyrase or other gyrase-like activities. Particular emphasis is made on the preparation of a relaxed plasmid as initial DNA substrate, on the distinction of constrained and unconstrained DNA supercoils, and on the measurement of the DNA supercoiling density achieved by gyrase activity.
Topics: Animals; Cattle; DNA Gyrase; DNA, Superhelical; Electrophoresis, Agar Gel; Humans; Substrate Specificity
PubMed: 29971724
DOI: 10.1007/978-1-4939-8556-2_15 -
Structure (London, England : 1993) May 2020Most biological processes involve formation of transient complexes where binding of a ligand allosterically modulates function. The ccd toxin-antitoxin system is...
Most biological processes involve formation of transient complexes where binding of a ligand allosterically modulates function. The ccd toxin-antitoxin system is involved in plasmid maintenance and bacterial persistence. The CcdA antitoxin accelerates dissociation of CcdB from its complex with DNA gyrase, binds and neutralizes CcdB, but the mechanistic details are unclear. Using a series of experimental and computational approaches, we demonstrate the formation of transient ternary and quaternary CcdA:CcdB:gyrase complexes and delineate the molecular steps involved in the rejuvenation process. Binding of region 61-72 of CcdA to CcdB induces the vital structural and dynamic changes required to facilitate dissociation from gyrase, region 50-60 enhances the dissociation process through additional allosteric effects, and segment 37-49 prevents gyrase rebinding. This study provides insights into molecular mechanisms responsible for recovery of CcdB-poisoned cells from a persister-like state. Similar methodology can be used to characterize other important transient, macromolecular complexes.
Topics: Bacterial Proteins; Bacterial Toxins; Binding Sites; Cysteine; DNA Gyrase; Fluorescence Resonance Energy Transfer; Models, Molecular; Multiprotein Complexes; Mutation; Surface Plasmon Resonance
PubMed: 32294467
DOI: 10.1016/j.str.2020.03.006