Four Ways to Skin a Cat: Inhibition of Bacterial Topoisomerases Leading to the Clinic

Basarab, Gregory S.

doi:10.1007/7355_2017_7

Cited by 10 publications

(51 citation statements)

References 93 publications

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“…The major band was isolated and contained a mixture of isomers. The mixture was separated using chiral chromatography (hexane:EtOH (2R,4S,4aS) -8-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-11-fluoro-2,4-dimethyl-1,2,4,4atetrahydro-2'H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino [4,3-a]quinoline-5,5'-pyrimidine]-2 ',4',6'(1'H,3'H)-trione (10). Prepared following the preparation of 8 using 48c (481 mg, 1.…”

Section: Docking Model Generationmentioning

confidence: 99%

“…[8][9] FQs comprise the most widely prescribed class of topoisomerase inhibitor (Figure 1) and are used for the treatment of a variety of bacterial infections. 5,7,10 Three FQs -moxifloxacin, levofloxacin and gatifloxacin -are currently used as second-line TB treatments. These compounds bind to a complex wherein both strands of the DNA are cleaved, covalently bonded to the topoisomerases.…”

Section: Introductionmentioning

confidence: 99%

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Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

et al. 2022

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New antibiotics with either a novel mode-of-action (MoA) or novel mode-of-inhibition (MoI) are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug resistant Mycobacterium tuberculosis (Mtb), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to Phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., Compound 42 with an IC50 = 2.0) and lower Mtb MICs (0.49 µM for 42). Notably, 42 and analogues showed selective Mtb activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed and a structural hypothesis was built for SAR expansion.

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Section: Docking Model Generationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

et al. 2022

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“…Both enzymes are essential for bacterial cell growth and are responsible for regulating the topology of bacterial DNA. Over the past 50 years, several classes of inhibitors have been developed and advanced to either clinical trials or the market. , By far, the most medically and commercially successful of these are the quinolone antibiotics. − The first example of this class, nalidixic acid, can be traced to two parallel discovery efforts at Imperial Chemical Industries (ICI) and Sterling Drug during the late 1950s and early 1960s . Since then, nearly 30 analogues have been approved for clinical use worldwide.…”

Section: Introductionmentioning

confidence: 99%

“…Given the clinical importance of quinolone antibiotics, the discovery of DNA gyrase and topoisomerase IV inhibitors that can overcome quinolone resistance is an area of significant interest in antibacterial research. ,, Interest in this area was further bolstered by reports from Pfizer on a series of quinazolinediones ( e.g. , compound 3 , Figure ) that are capable of binding to and stabilizing DNA gyrase/topoisomerase IV cleavage complexes but do not rely on formation of a water–metal ion bridge interaction. − To date, there have been no reports of compounds from this series reaching the clinic.…”

Section: Introductionmentioning

confidence: 99%

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

Lapointe¹,

Skepper²,

Holder³

et al. 2021

J. Med. Chem.

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Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water–metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

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“…As such, there is significant interest in identifying inhibitors of these enzymes that are able to overcome target-based resistance to quinolones. [29][30][31] In a series of seminal publications and patents Pfizer described the discovery and optimization of 3aminoquinazolinediones [32][33][34] (e.g., compound 2, Figure 1) that are capable of binding to and stabilizing DNA gyrase/topoisomerase IV cleavage complexes in the absence of the key watermetal ion bridge interaction that characterizes classical quinolone binding. 14-18, 35, 36 Lead compounds in this series exhibited little or no cross-resistance with quinolones.…”

Section: Introductionmentioning

confidence: 99%

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

et al. 2020

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Since their discovery over five decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC Quinolone Resistance Determining Region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1H)-ones, exemplified by 34, that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gramnegative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex, but does not form significant contacts with residues in the Quinolone Resistance Determining Region.

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Four Ways to Skin a Cat: Inhibition of Bacterial Topoisomerases Leading to the Clinic

Cited by 10 publications

References 93 publications

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

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

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria

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