Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase† †The authors declare no competing interests. ‡ ‡The authors declare no competing financial interest. § §Electronic supplementary information (ESI) available: Tables, figures, bacterial strain information and compound purity data. See DOI: 10.1039/c7md00012j

• Published in: MedChemComm Vol. 8; no. 5; pp. 942 - 951
• Main Authors: Hurley, Katherine A., Santos, Thiago M. A., Fensterwald, Molly R., Rajendran, Madhusudan, Moore, Jared T., Balmond, Edward I., Blahnik, Brice J., Faulkner, Katherine C., Foss, Marie H., Heinrich, Victoria A., Lammers, Matthew G., Moore, Lucas C., Reynolds, Gregory D., Shearn-Nance, Galen P., Stearns, Brian A., Yao, Zi W., Shaw, Jared T., Weibel, Douglas B.
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 27-02-2017
• Subjects: Chemistry
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c7md00012j

New gyramide antibiotics with reduced drug efflux and improved antibiotic activity against pathogenic bacteria.
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 (IC
50
s 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.