Synthesis of novel 2-aminobenzothiazole derivatives as potential antimicrobial agents with dual DNA gyrase/topoisomerase IV inhibition

ABSTRACT DNA gyrase and topoisomerase IV (topo IV) are the two essential type II topoisomerases of Escherichia coli. Gyrase is responsible for maintaining negative supercoiling of the bacterial chromosome, whereas topo IV's primary role is in disentangling daughter chromosomes following DNA replication. Coumarins, such as novobiocin, are wide-spectrum antimicrobial agents that primarily interfere with DNA gyrase. In this work we designed an alteration in the ParE subunit of topo IV at a site homologous to that which confers coumarin resistance in gyrase. This parE mutation renders the encoded topo IV approximately 40-fold resistant to inhibition by novobiocin in vitro and imparts a similar resistance to inhibition of topo IV-mediated relaxation of supercoiled DNA in vivo. We conclude that topo IV is a secondary target of novobiocin and that it is very likely to be inhibited by the same mechanism as DNA gyrase.

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A Mutation in Escherichia coli DNA Gyrase Conferring Quinolone Resistance Results in Sensitivity to Drugs Targeting Eukaryotic Topoisomerase II

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.12.4495-4504.2004 ◽

2004 ◽

Vol 48 (12) ◽

pp. 4495-4504 ◽

Cited By ~ 25

Author(s):

Thomas Gruger ◽

John L. Nitiss ◽

Anthony Maxwell ◽

E. Lynn Zechiedrich ◽

Peter Heisig ◽

...

Keyword(s):

Escherichia Coli ◽

Dna Cleavage ◽

Topoisomerase Ii ◽

Antimicrobial Agents ◽

Dna Gyrase ◽

Dna Supercoiling ◽

Quinolone Resistance ◽

Site Directed Mutagenesis ◽

Type Ii ◽

Topoisomerase Iv

ABSTRACT Fluoroquinolones are broad-spectrum antimicrobial agents that target type II topoisomerases. Many fluoroquinolones are highly specific for bacterial type II topoisomerases and act against both DNA gyrase and topoisomerase IV. In Escherichia coli, mutations causing quinolone resistance are often found in the gene that encodes the A subunit of DNA gyrase. One common site for resistance-conferring mutations alters Ser83, and mutations to Leu or Trp result in high levels of resistance to fluoroquinolones. In the present study we demonstrate that the mutation of Ser83 to Trp in DNA gyrase (GyrS83W) also results in sensitivity to agents that are potent inhibitors of eukaryotic topoisomerase II but that are normally inactive against prokaryotic enzymes. Epipodophyllotoxins, such as etoposide, teniposide and amino-azatoxin, inhibited the DNA supercoiling activity of GyrS83W, and the enzyme caused elevated levels of DNA cleavage in the presence of these agents. The DNA sequence preference for GyrS83W-induced cleavage sites in the presence of etoposide was similar to that seen with eukaryotic type II topoisomerases. Introduction of the GyrS83W mutation in E. coli strain RFM443-242 by site-directed mutagenesis sensitized it to epipodophyllotoxins and amino-azatoxin. Our results demonstrate that sensitivity to agents that target topoisomerase II is conserved between prokaryotic and eukaryotic enzymes, suggesting that drug interaction domains are also well conserved and likely occur in domains important for the biochemical activities of the enzymes.

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Delafloxacin, Finafloxacin, and Zabofloxacin: Novel Fluoroquinolones in the Antibiotic Pipeline

Antibiotics ◽

10.3390/antibiotics10121506 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1506

Author(s):

Béla Kocsis ◽

Dániel Gulyás ◽

Dóra Szabó

Keyword(s):

Broad Spectrum ◽

Bacterial Infections ◽

Chemical Structure ◽

Antimicrobial Agents ◽

Treatment Options ◽

Dna Gyrase ◽

Daily Practice ◽

Molecular Surface ◽

Chronic Obstructive ◽

Topoisomerase Iv

Novel antimicrobial agents, approved for clinical use in past years, represent potential treatment options for various infections. In this review, we summarize the most important medical and microbiological features of three recently approved fluoroquinolones, namely delafloxacin, finafloxacin, and zabofloxacin. Delafloxacin possesses an anionic chemical structure, and represents broad-spectrum activity, as it targets both bacterial DNA gyrase and topoisomerase IV enzymes of gram-positive and gram-negative bacteria with equal affinity. Its molecular surface is larger than that of other fluoroquinolones, and it has enhanced antibacterial efficacy in acidic environments. Delafloxacin has been approved to treat acute bacterial skin and skin-structure infections, as well as community-acquired bacterial pneumonia. Finafloxacin has a zwitterionic chemical structure, and targets both DNA gyrase and topoisomerase IV enzymes. This enables a broad antibacterial spectrum; however, finafloxacin has so far only been approved in ear-drops to treat bacterial otitis externa. Zabofloxacin is also a broad-spectrum fluoroquinolone agent, and was first approved in South Korea to treat acute bacterial exacerbation of chronic obstructive pulmonary disease. The introduction of these novel fluoroquinolones into daily practice extends the possible indications of antibiotics into different bacterial infections, and provides treatment options in difficult-to-treat infections. However, some reports of delafloxacin resistance have already appeared, thus underlining the importance of the prudent use of antibiotics.

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Design, Synthesis and Antimicrobial Evaluation of New Norfloxacin-Naphthoquinone Hybrid Molecules

Proceedings ◽

10.3390/ecsoc-23-06480 ◽

2019 ◽

Vol 41 (1) ◽

pp. 9 ◽

Cited By ~ 1

Author(s):

Andrea Defant ◽

Alessandro Vozza ◽

Ines Mancini

Keyword(s):

Bacterial Infections ◽

Antimicrobial Agents ◽

Biological Activities ◽

Dna Gyrase ◽

Structural Features ◽

Therapeutic Agents ◽

Topoisomerase Iv ◽

Design Synthesis ◽

Biological Targets ◽

Hybrid Molecules

Although the wide arsenal of drugs available to treat bacterial infections, emerging drug-resistant bacterial pathogens have recently highlighted an urgent need to find new more effective and less toxic therapeutic agents. Fluoroquinolones, including norfloxacin, are antibiotics showing a concentration-dependent bactericidal capacity due to the activity inhibition of DNA-gyrase and topoisomerase IV, which are enzymes essential for bacterial DNA replication. Naphthoquinones are secondary metabolites showing different biological activities, including cytotoxic, antibacterial and antifungal effects. In particular, the efficacy of natural and synthetic 1,4-naphthoquinone derivatives is likely due to their oxidizing/reducing capability, through which they destroy cellular targets as nucleic acids. Hybrid molecules are produced combining structural features of two or more bioactive compounds, in order to obtain new therapeutic agents able, not only to reduce undesirable side effects of the parent drugs, but also to inhibit more biological targets, hopefully with a better therapeutic property than the administration of combined single-target drugs. With the aim to apply this strategy in the study of new potential antimicrobial agents, we have synthesized four hybrid molecules by the reaction of norfloxacin with suitable quinones and their activities have been evaluated against both bacteria and fungi, in comparison with synthetic precursors. The experimental data are supported by docking calculations on S. aureus DNA-gyrase, discussing the interactions involved for each hybrid molecule, in comparison with norfloxacin and the original ligand moxifloxacin.

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In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.4.1228-1237.2006 ◽

2006 ◽

Vol 50 (4) ◽

pp. 1228-1237 ◽

Cited By ~ 56

Author(s):

Nagraj Mani ◽

Christian H. Gross ◽

Jonathan D. Parsons ◽

Brian Hanzelka ◽

Ute Müh ◽

...

Keyword(s):

Bacterial Resistance ◽

Wide Spectrum ◽

Dna Gyrase ◽

Antibacterial Activities ◽

Mechanisms Of Action ◽

Fluoroquinolone Resistance ◽

Topoisomerase Iv ◽

Low Frequencies

ABSTRACT Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

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Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.1c00375 ◽

2021 ◽

Author(s):

Guillaume Lapointe ◽

Colin K. Skepper ◽

Lauren M. Holder ◽

Duncan Armstrong ◽

Cornelia Bellamacina ◽

...

Keyword(s):

Dna Gyrase ◽

Topoisomerase Iv ◽

Gram Positive ◽

Gram Positive Bacteria

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In VitroandIn VivoCharacterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00619-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4830-4839 ◽

Cited By ~ 12

Author(s):

Christopher M. Tan ◽

Charles J. Gill ◽

Jin Wu ◽

Nathalie Toussaint ◽

Jingjun Yin ◽

...

Keyword(s):

Broad Spectrum ◽

Antibacterial Agents ◽

Cell Activity ◽

Dna Gyrase ◽

Topoisomerase Iv ◽

Bacterial Dna ◽

Whole Cell ◽

Content Type

ABSTRACTOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, andin vivocharacterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV fromStaphylococcus aureusandEscherichia coliand displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergencein vitroat concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activityin vitroandin vivo.

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