N-Benzyl-3-sulfonamidopyrrolidines are a New Class of Bacterial DNA Gyrase Inhibitors - PubMed (original) (raw)

N-Benzyl-3-sulfonamidopyrrolidines are a New Class of Bacterial DNA Gyrase Inhibitors

Marie H Foss et al. ACS Med Chem Lett. 2011.

Abstract

This paper characterizes N-benzyl-3-sulfonamidopyrrolidines (gyramides) as DNA gyrase inhibitors. Gyramide A was previously shown to exhibit antimicrobial activity that suggested it inhibited bacterial cell division. In this study, we conducted target identification studies and identified DNA gyrase as the primary target of gyramide A. The gyramide A resistance-determining region in DNA gyrase is adjacent to the DNA cleavage gate and is a new site for inhibitor design. We studied the antibiotic effects of gyramides A-C in combination with the Gram-negative efflux pump inhibitor MC-207,110 (60 μM). The gyramides had a minimum inhibitory concentration of 10-40 μM against Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, and Streptococcus pneumoniae; the compounds were ineffective against Enterococcus faecalis. The IC(50) of gyramides A-C against E. coli DNA gyrase was 0.7- 3.3 μM. The N-benzyl-3-sulfonamidopyrrolidines described in this manuscript represent a starting point for development of antibiotics that bind a new site in DNA gyrase.

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Figures

Figure 1

Figure 1

Chemical structures of gyramides 1−3. The arrow indicates the chiral center in the gyramides.

Figure 2

Figure 2

Location of amino acids that confer resistance to 1. The E. coli DNA gyrase structure from ref (22) (PDB 3NUH). The cartoon shows the GyrA subunit in beige, the GyrB subunit in gray, and the DNA duplex with the backbone and bases represented by lines. The DNA duplex was modeled to the structure by alignment of the GyrA subunit to the structure from ref (10) (PDB 2XCS). The atoms of several different amino acid side chains are displayed as colored spheres. The active-site tyrosine is green, amino acids that were identified in mutants that are resistant to quinolones are red, and amino acids that confer resistance to 1 are blue. The image was generated using PyMol.

Figure 3

Figure 3

Inhibition of DNA gyrase supercoiling activity by 1−3. The table summarizes the IC50 values for ciprofloxacin and gyramides (R)-1, 2, 3, and (S)-1. A representative gel obtained from the analysis of the inhibition of DNA gyrase supercoiling activity is shown. The open circle graphic represents relaxed closed circular DNA, the coiled graphic signifies supercoiled DNA, and the arrow shows the direction of increased mobility of supercoiled DNA states. Supercoiled (“S”), linear (“L”), and relaxed (“R”) pUC19 controls are labeled above the lanes. Gel data for assays with 2 and 3 are shown (in μM); the label “C” indicates the lane for the solvent control. The lane labeled “CIP” represents treatment with 0.7 μM ciprofloxacin, which is the IC50 for ciprofloxacin in our assay.

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