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

ABSTRACT: Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.

SUBMITTER: O'Dowd H

PROVIDER: S-EPMC4499827 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

O'Dowd Hardwin H Shannon Dean E DE Chandupatla Kishan R KR Dixit Vaishali V Engtrakul Juntyma J JJ Ye Zhengqi Z Jones Steven M SM O'Brien Colleen F CF Nicolau David P DP Tessier Pamela R PR Crandon Jared L JL Song Bin B Macikenas Dainius D Hanzelka Brian L BL Le Tiran Arnaud A Bennani Youssef L YL Charifson Paul S PS Grillot Anne-Laure AL

ACS medicinal chemistry letters 20150622 7

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent ...[more]

PMID: 26191374

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Project description:Heteroaryl isothiazolones (HITZs) are antibacterial agents that display excellent in vitro activity against Staphylococcus aureus. We recently identified a series of these compounds that show potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA). We report here the results of in vitro resistance studies that reveal potential underlying mechanisms of action. HITZs selected gyrA mutations exclusively in first-step mutants of wild-type S. aureus, indicating that in contrast to the case with most quinolones, DNA gyrase is the primary target. The compounds displayed low mutation frequencies (10(-9) to 10(-10)) at concentrations close to the MICs and maintained low MICs (< or =0.016 microg/ml) against mutants with single mutations in either gyrA or grlA (parC). These data suggested that HITZs possess significant inhibitory activities against target enzymes, DNA gyrase and topoisomerase IV. This dual-target inhibition was supported by low 50% inhibitory concentrations against topoisomerase IV as measured in a decatenation activity assay and against DNA gyrase as measured in a supercoiling activity assay. Good antibacterial activities (< or =1 microg/ml) against staphylococcal gyrA grlA double mutants, as well as low frequencies (10(-9) to 10(-10)) of selection of still higher-level mutants, also suggested that HITZs remained active against mutant enzymes. We further demonstrated that HITZs exhibit good inhibition of both S. aureus mutant enzymes and thus continue to possess a novel dual-targeting mode of action against these mutant strains. In stepwise acquisition of mutations, HITZs selected quinolone resistance determining region mutations gyrA(Ser84Leu), grlA(Ser80Phe), grlA(Ala116Val), and gyrA(Glu88Lys) sequentially, suggesting that the corresponding amino acids are key amino acids involved in the binding of HITZs to topoisomerases. The overall profile of these compounds suggests the potential utility of HITZs in combating infections caused by S. aureus, including multidrug-resistant MRSA.

Project description:DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050 μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112 nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170 nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC50 value of 11 µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.

Dataset Information

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

Publications

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

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