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Molecules (Basel, Switzerland) Dec 2020Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools... (Review)
Review
Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools in the armoury of clinical treatments. FQs target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, where they stabilise a covalent enzyme-DNA complex in which the DNA is cleaved in both strands. This leads to cell death and turns out to be a very effective way of killing bacteria. However, resistance to FQs is increasingly problematic, and alternative compounds are urgently needed. Here, we review the mechanisms of action of FQs and discuss the potential pathways leading to cell death. We also discuss quinolone resistance and how quinolone treatment can lead to resistance to non-quinolone antibiotics.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Humans; Quinolones
PubMed: 33271787
DOI: 10.3390/molecules25235662 -
Frontiers in Public Health 2022For around three decades, the fluoroquinolone (FQ) antibiotic ciprofloxacin has been used to treat a range of diseases, including chronic otorrhea, endocarditis, lower... (Review)
Review
For around three decades, the fluoroquinolone (FQ) antibiotic ciprofloxacin has been used to treat a range of diseases, including chronic otorrhea, endocarditis, lower respiratory tract, gastrointestinal, skin and soft tissue, and urinary tract infections. Ciprofloxacin's main mode of action is to stop DNA replication by blocking the A subunit of DNA gyrase and having an extra impact on the substances in cell walls. Available in intravenous and oral formulations, ciprofloxacin reaches therapeutic concentrations in the majority of tissues and bodily fluids with a low possibility for side effects. Despite the outstanding qualities of this antibiotic, , and have all shown an increase in ciprofloxacin resistance over time. The rise of infections that are resistant to ciprofloxacin shows that new pharmacological synergisms and derivatives are required. To this end, ciprofloxacin may be more effective against the biofilm community of microorganisms and multi-drug resistant isolates when combined with a variety of antibacterial agents, such as antibiotics from various classes, nanoparticles, natural products, bacteriophages, and photodynamic therapy. This review focuses on the resistance mechanisms of bacteria against ciprofloxacin and new approaches for enhancing its efficacy.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Bacteria; Fluoroquinolones
PubMed: 36620240
DOI: 10.3389/fpubh.2022.1025633 -
MedChemComm Oct 2019The quinolone antibiotics arose in the early 1960s, with the first examples possessing a narrow-spectrum of activity with unfavorable pharmacokinetic properties. Over... (Review)
Review
The quinolone antibiotics arose in the early 1960s, with the first examples possessing a narrow-spectrum of activity with unfavorable pharmacokinetic properties. Over time, the development of new quinolone antibiotics has led to improved analogues with an expanded spectrum and high efficacy. Nowadays, quinolones are widely used for treating a variety of infections. Quinolones are broad-spectrum antibiotics that are active against both Gram-positive and Gram-negative bacteria, including mycobacteria, and anaerobes. They exert their actions by inhibiting bacterial nucleic acid synthesis through disrupting the enzymes topoisomerase IV and DNA gyrase, and by causing breakage of bacterial chromosomes. However, bacteria have acquired resistance to quinolones, similar to other antibacterial agents, due to the overuse of these drugs. Mechanisms contributing to quinolone resistance are mediated by chromosomal mutations and/or plasmid gene uptake that alter the topoisomerase targets, modify the quinolone, and/or reduce drug accumulation by either decreased uptake or increased efflux. This review discusses the development of this class of antibiotics in terms of potency, pharmacokinetics and toxicity, along with the resistance mechanisms which reduce the quinolones' activity against pathogens. Potential strategies for future generations of quinolone antibiotics with enhanced activity against resistant strains are suggested.
PubMed: 31803393
DOI: 10.1039/c9md00120d -
Sheng Wu Gong Cheng Xue Bao = Chinese... Aug 2022(Ashby) Downson is a quarantine pest for importing plants to China that causes leaf scald bacterial disease on sugarcane. . produces a potent phytotoxin/antibiotic... (Review)
Review
(Ashby) Downson is a quarantine pest for importing plants to China that causes leaf scald bacterial disease on sugarcane. . produces a potent phytotoxin/antibiotic called albicidin. As a pathogenic factor, albicidin causes typical white leaf stripes by inhibiting plastid DNA gyrase and disturbing chloroplast differentiation. Meanwhile, the antibacterial activity of albicidin gives . a competitive advantage against rival bacteria during their colonization. Furthermore, albicidin has a rapid bactericidal activity against a variety of Gram-positive and Gram-negative pathogenic bacteria of human species at nanomolar concentrations, making it a potential antimicrobial drug for clinical application. This article reviews the advances of albicidin from the aspects of its molecular structure, traditional extraction methods, mechanism of action, biosynthetic genes and processes, chemical synthesis method and improvement, in order to provide insights into the prevention and treatment of the sugarcane leaf scald disease, and the development of new antibiotics.
Topics: Anti-Bacterial Agents; China; Humans; Organic Chemicals; Xanthomonas
PubMed: 36002407
DOI: 10.13345/j.cjb.210832 -
The Journal of Biological Chemistry May 2020The double-helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and... (Review)
Review
The double-helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and compaction. However, these design advantages come at the cost of having to evolve and maintain a cellular machinery that can manipulate a long polymeric molecule that readily becomes topologically entangled whenever it has to be opened for translation, replication, or repair. If such a machinery fails to eliminate detrimental topological entanglements, utilization of the information stored in the DNA double helix is compromised. As a consequence, the use of B-form DNA as the carrier of genetic information must have co-evolved with a means to manipulate its complex topology. This duty is performed by DNA topoisomerases, which therefore are, unsurprisingly, ubiquitous in all kingdoms of life. In this review, we focus on how DNA topoisomerases catalyze their impressive range of DNA-conjuring tricks, with a particular emphasis on DNA topoisomerase III (TOP3). Once thought to be the most unremarkable of topoisomerases, the many lives of these type IA topoisomerases are now being progressively revealed. This research interest is driven by a realization that their substrate versatility and their ability to engage in intimate collaborations with translocases and other DNA-processing enzymes are far more extensive and impressive than was thought hitherto. This, coupled with the recent associations of TOP3s with developmental and neurological pathologies in humans, is clearly making us reconsider their undeserved reputation as being unexceptional enzymes.
Topics: DNA Topoisomerases, Type I; DNA, B-Form; Humans; Nervous System Diseases
PubMed: 32277049
DOI: 10.1074/jbc.REV120.008286 -
Biomedicines Jan 2023Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new... (Review)
Review
Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quinolone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or develop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics.
PubMed: 36830908
DOI: 10.3390/biomedicines11020371 -
Antibiotics (Basel, Switzerland) Jul 2023The extensive use of fluoroquinolones has been consequently accompanied by the emergence of bacterial resistance, which triggers the necessity to discover new compounds.... (Review)
Review
The extensive use of fluoroquinolones has been consequently accompanied by the emergence of bacterial resistance, which triggers the necessity to discover new compounds. Delafloxacin is a brand-new anionic non-zwitterionic fluoroquinolone with some structural particularities that give it attractive proprieties: high activity under acidic conditions, greater in vitro activity against Gram-positive bacteria-even those showing resistance to currently-used fluoroquinolones-and nearly equivalent affinity for both type-II topoisomerases (i.e., DNA gyrase and topoisomerase IV). During phases II and III clinical trials, delafloxacin showed non-inferiority compared to standard-of-care therapy in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, which resulted in its approval in 2017 by the Food and Drug Administration for indications. Thanks to its overall good tolerance, its broad-spectrum in vitro activity, and its ease of use, it could represent a promising molecule for the treatment of bacterial infections.
PubMed: 37627661
DOI: 10.3390/antibiotics12081241 -
ELife Jun 2024DNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active...
DNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active complex. DNA gyrase can loop DNA around the C-terminal domains (CTDs) of GyrA and pass one DNA duplex through a transient double-strand break (DSB) established in another duplex. This results in the conversion from a positive (+1) to a negative (-1) supercoil, thereby introducing negative supercoiling into the bacterial genome by steps of 2, an activity essential for DNA replication and transcription. The strong protein interface in the GyrA dimer must be broken to allow passage of the transported DNA segment and it is generally assumed that the interface is usually stable and only opens when DNA is transported, to prevent the introduction of deleterious DSBs in the genome. In this paper, we show that DNA gyrase can exchange its DNA-cleaving interfaces between two active heterotetramers. This so-called interface 'swapping' (IS) can occur within a few minutes in solution. We also show that bending of DNA by gyrase is essential for cleavage but not for DNA binding per se and favors IS. Interface swapping is also favored by DNA wrapping and an excess of GyrB. We suggest that proximity, promoted by GyrB oligomerization and binding and wrapping along a length of DNA, between two heterotetramers favors rapid interface swapping. This swapping does not require ATP, occurs in the presence of fluoroquinolones, and raises the possibility of non-homologous recombination solely through gyrase activity. The ability of gyrase to undergo interface swapping explains how gyrase heterodimers, containing a single active-site tyrosine, can carry out double-strand passage reactions and therefore suggests an alternative explanation to the recently proposed 'swivelling' mechanism for DNA gyrase (Gubaev et al., 2016).
Topics: DNA Gyrase; Protein Multimerization; DNA, Bacterial; Escherichia coli; DNA
PubMed: 38856655
DOI: 10.7554/eLife.86722 -
Protein Science : a Publication of the... Oct 2021DNA supercoiling controls a variety of cellular processes, including transcription, recombination, chromosome replication, and segregation, across all domains of life.... (Review)
Review
DNA supercoiling controls a variety of cellular processes, including transcription, recombination, chromosome replication, and segregation, across all domains of life. As a physical property, DNA supercoiling alters the double helix structure by under- or over-winding it. Intriguingly, the evolution of DNA supercoiling reveals both similarities and differences in its properties and regulation across the three domains of life. Whereas all organisms exhibit local, constrained DNA supercoiling, only bacteria and archaea exhibit unconstrained global supercoiling. DNA supercoiling emerges naturally from certain cellular processes and can also be changed by enzymes called topoisomerases. While structurally and mechanistically distinct, topoisomerases that dissipate excessive supercoils exist in all domains of life. By contrast, topoisomerases that introduce positive or negative supercoils exist only in bacteria and archaea. The abundance of topoisomerases is also transcriptionally and post-transcriptionally regulated in domain-specific ways. Nucleoid-associated proteins, metabolites, and physicochemical factors influence DNA supercoiling by acting on the DNA itself or by impacting the activity of topoisomerases. Overall, the unique strategies that organisms have evolved to regulate DNA supercoiling hold significant therapeutic potential, such as bactericidal agents that target bacteria-specific processes or anticancer drugs that hinder abnormal DNA replication by acting on eukaryotic topoisomerases specialized in this process. The investigation of DNA supercoiling therefore reveals general principles, conserved mechanisms, and kingdom-specific variations relevant to a wide range of biological questions.
Topics: Archaea; Bacteria; DNA Replication; DNA, Archaeal; DNA, Bacterial; DNA, Superhelical; Evolution, Molecular
PubMed: 34398513
DOI: 10.1002/pro.4171 -
The Journal of Biological Chemistry Dec 2023Macromolecular crowding, manifested by high concentrations of proteins and nucleic acids in living cells, significantly influences biological processes such as enzymatic...
Macromolecular crowding, manifested by high concentrations of proteins and nucleic acids in living cells, significantly influences biological processes such as enzymatic reactions. Studying these reactions in vitro, using agents such as polyetthylene glycols (PEGs) and polyvinyl alcohols (PVAs) to mimic intracellular crowding conditions, is essential due to the notable differences from enzyme behaviors observed in diluted aqueous solutions. In this article, we studied Mycobacterium tuberculosis (Mtb) DNA gyrase under macromolecular crowding conditions by incorporating PEGs and PVAs into the DNA supercoiling reactions. We discovered that high concentrations of potassium glutamate, glycine betaine, PEGs, and PVA substantially stimulated the DNA supercoiling activity of Mtb DNA gyrase. Steady-state kinetic studies showed that glycine betaine and PEG400 significantly reduced the K of Mtb DNA gyrase and simultaneously increased the V or k of Mtb DNA gyrase for ATP and the plasmid DNA molecule. Molecular dynamics simulation studies demonstrated that PEG molecules kept the ATP lid of DNA gyrase subunit B in a closed or semiclosed conformation, which prevented ATP molecules from leaving the ATP-binding pocket of DNA gyrase subunit B. The stimulation of the DNA supercoiling activity of Mtb DNA gyrase by these molecular crowding agents likely results from a decrease in water activity and an increase in excluded volume.
Topics: DNA Gyrase; Mycobacterium tuberculosis; Betaine; Kinetics; Adenosine Triphosphate; DNA; DNA, Superhelical
PubMed: 37944619
DOI: 10.1016/j.jbc.2023.105439