Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase

Abstract

Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs—from a library of 183 derivatives—that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (Escherichia coli, Shigella flexneri, and Salmonella enterica; 3 of 10 wild-type strains tested) and gram-positive bacteria (Bacillus spp., Enterococcus spp., Staphylococcus spp., and Streptococcus spp.; all 9 of the wild-type strains tested). E. coli strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC50s of 47–170 nM) but do not alter the enzyme’s ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (gyrA and gyrB genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.

SNAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design

“…Yield 52.4 mg (79%); brownish gum; 1 ) δ 160.7, 147.8 (q, J = 3.4 Hz), 137.7 (q, J = 2.9 Hz), 124.1, 123.6 (q, J = 272 Hz), 117.0 (q, J = 33.2 Hz), 65. 1,51.8 (d,J = 13.6 Hz), 50.2 (d, J = 13.8 Hz), 48.6, 36.0 (d, J = 71.5 Hz), 31.4, 24.2 (d, J = 2.1 Hz), 24.0, 23.9 (d, J = 2.4 Hz), 16.2, 13.9 (d, J = 10.2 Hz), 13.4 (d, J = 10.2 Hz), 4.6, 2.5; 19 1H),7.06 (d,J = 7.7 Hz,1H),1H),6.73 (d,J = 8.0 Hz,1H),6.65 (d,J = 9.1 Hz,1H),1H),1H),2H),2H),3H),3H), 1.91−1.72 (m, 2H); 13 C{ 1 H} NMR (126 MHz, DMSO-d 6 ) δ 157. 7, 154.6, 147.5, 139.9, 135.3, 131.3, 129.6, 129.5, 128.8, 128.5, 124.4, 122.5, 120.2, 116.5, 106.1, 62.6, 60.4, 53.6, 50.1, 47.3, 46.6, 44.3, 29.2 H,5.24;N,8.40;S,6.41;Cl,7.09.…”

“…Therefore, 16 available sulfonyl fluorides, 13{1−16}, bearing a sufficiently S N Arreactive center and five model amines, 14{1−5}, were selected to study the process more thoroughly at lower temperatures (Table 1). The reaction outcome was monitored by LC-MS. For the case of fluorohetarene sulfonyl flurides 13{1−9}, this method alone was not sufficient to establish the reaction chemoselectivity, and the structure of corresponding products 15 and 16 was confirmed by 19 F NMR spectroscopy because the SO 2 F and hetaryl fluoride signals can be easily distinguished by their chemical shifts. It was found that when the reaction was performed in the presence of i-Pr 2 NEt in CH 3 CN at ambient temperature, arylation was either dominant or prevailing in most cases.…”

CycA-Dependent Glycine Assimilation Is Connected to Novobiocin Susceptibility in Escherichia coli

“…As a member of the coumarin family of antimicrobial drugs, novobiocin (NOV) inhibits the ATPase activity of bacterial DNA gyrase and topoisomerase IV ( 1 ), which are both validated drug targets. Although NOV has been withdrawn from the marketplace since 2011, pharmaceutical companies are still developing other ATPase inhibitors ( 2 , 3 ). Low permeability across the outer membrane has been considered the major reason why NOV was ineffective against Gram-negative bacteria.…”

Design of a novel DNA Gyrase B inhibitor with a rhodanine scaffold: in silico and in vitro approaches

“…In this accord, bacterial gyrase targeted therapeutics is unique since it is the universal enzyme required for bacterial survival and is absent in higher eukaryotes (14) . DNA gyrase (gyrase), a member of bacterial topoisomerases is known to control the DNA dependent processes by introducing transient breaks to both DNA strands (15) , in addition to relieving the torsional tension, by introducing negative supercoils to the DNA molecule (16). DNA gyrase is a heterotetrameric protein composed of two GyrA subunits where the DNA cleavage site is located, and two GyrB subunits that provide the energy necessary for the catalytic function of the enzyme through ATP hydrolysis (4) .…”