Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV

O'Dowd, Hardwin; Shannon, Dean; Chandupatla, Kishan R.; Dixit, Vaishali; Engtrakul, Juntyma J.; Ye, Zhengqi; Jones, Steven M.; O’Brien, Colleen; Nicolau, David P.; Tessier, Pamela R.; Crandon, Jared L.; Song, Bin; Macikenas, Dainius; Hanzelka, Brian L.; LeTiran, Arnaud; Bennani, Youssef L.; Charifson, Paul S.; Grillot, Anne‐Laure

doi:10.1021/acsmedchemlett.5b00196

Cited by 21 publications

(12 citation statements)

References 32 publications

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“…9 Thus, the selectivity of targeting prokaryotic topoisomerase II, the potential of dual targeting, and the well-known structure of these enzymes makes both DNA gyrase and topoisomerase IV attractive targets in the challenging search for new antibacterial compounds. [9][10][11][12][13][14][15][16][17] DNA gyrase and topoisomerase IV have been recognized as targets of aminocoumarin and quinolone classes of antibacterial compounds. However, these two classes of inhibitors target different parts of the enzymes.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors

et al. 2016

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Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV from both E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compounds possessed weak antibacterial activity against Gram-positive bacteria. These results provide a basis for structure-based optimization toward dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.

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Section: Introductionmentioning

confidence: 99%

Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors

et al. 2016

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“…Taking into account the planar rigid structure similarity between 15a and quinolones, we initially examined its effects on gyrase and topoisomerase (topo) IV activities of S. aureus by gyrase-mediated supercoiling of relaxed DNA assay and topo IV-mediated decatenation of kinetoplast DNA (kDNA) assay [ 19 , 20 ], respectively. As shown in Figure 3 , topo IV-mediated decatenation activity was significantly inhibited in a concentration-dependent manner after treatment of 15a .…”

Section: Resultsmentioning

confidence: 99%

Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA

Yang

Wei

et al. 2019

Molecules

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Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25–0.5 μg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg−1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 μg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.

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“…DS-2969b and DS11960558 were also found to be efficacious against neutropenic rat thigh infections when they were administered by the intravenous route. O'Dowd et al identified a bacterial topoisomerase inhibitor that exhibited bactericidal potential at 60 mg/kg/day in a murine pneumonia model (34). DS-2969b and DS11960558 showed bactericidal effects at doses lower than 60 mg/kg/day; however, the animal model was different.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

Barman

Kumar

Mathur

et al. 2018

Antimicrob Agents Chemother

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DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the activity of DS-2969b and the activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except for and DS-2969b was active against MRSA with an MIC of 0.25 μg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 × 10 in all four isolates at 4× MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC () correlated best with efficacy, and the static percent was 43 to 49%. A sufficient was observed in a phase 1 multiple-ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to-oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid.

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Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV

Cited by 21 publications

References 32 publications

Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors

Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors

Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA

In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus

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