Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology

Manohary Rajendram, Katherine A. Hurley, Marie H. Foss, Kelsey M. Thornton, Jared T. Moore, Jared T. Shaw, Douglas B. Weibel

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Antibiotics targeting DNA gyrase have been a clinical success story for the past half-century, and the emergence of bacterial resistance has fueled the search for new gyrase inhibitors. In this paper we demonstrate that a new class of gyrase inhibitors, the gyramides, are bacteriostatic agents that competitively inhibit the ATPase activity of Escherichia coli gyrase and produce supercoiled DNA in vivo. E. coli cells treated with gyramide A have abnormally localized, condensed chromosomes that blocks DNA replication and interrupts chromosome segregation. The resulting alterations in DNA topology inhibit cell division through a mechanism that involves the SOS pathway. Importantly, gyramide A is a specific inhibitor of gyrase and does not inhibit the closely related E. coli enzyme topoisomerase IV. E. coli mutants with reduced susceptibility to gyramide A do not display cross-resistance to ciprofloxacin and novobiocin. The results demonstrate that the gyramides prevent bacterial growth by a mechanism in which the topological state of chromosomes is altered and halts DNA replication and segregation. The specificity and activity of the gyramides for inhibiting gyrase makes these compounds important chemical tools for studying the mechanism of gyrase and the connection between DNA topology and bacterial cell division.

Original languageEnglish (US)
Pages (from-to)1312-1319
Number of pages8
JournalACS Chemical Biology
Volume9
Issue number6
DOIs
StatePublished - Jun 20 2014

Fingerprint

DNA Gyrase
Chromosomes
Escherichia coli
Topology
Growth
DNA Replication
Cell Division
DNA
DNA Topoisomerase IV
Cells
Novobiocin
Superhelical DNA
Bacterial DNA
Chromosome Segregation
Chemical compounds
Ciprofloxacin
Adenosine Triphosphatases
Anti-Bacterial Agents
Enzymes
gyramide A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Rajendram, M., Hurley, K. A., Foss, M. H., Thornton, K. M., Moore, J. T., Shaw, J. T., & Weibel, D. B. (2014). Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology. ACS Chemical Biology, 9(6), 1312-1319. https://doi.org/10.1021/cb500154m

Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology. / Rajendram, Manohary; Hurley, Katherine A.; Foss, Marie H.; Thornton, Kelsey M.; Moore, Jared T.; Shaw, Jared T.; Weibel, Douglas B.

In: ACS Chemical Biology, Vol. 9, No. 6, 20.06.2014, p. 1312-1319.

Research output: Contribution to journalArticle

Rajendram, M, Hurley, KA, Foss, MH, Thornton, KM, Moore, JT, Shaw, JT & Weibel, DB 2014, 'Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology', ACS Chemical Biology, vol. 9, no. 6, pp. 1312-1319. https://doi.org/10.1021/cb500154m
Rajendram M, Hurley KA, Foss MH, Thornton KM, Moore JT, Shaw JT et al. Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology. ACS Chemical Biology. 2014 Jun 20;9(6):1312-1319. https://doi.org/10.1021/cb500154m
Rajendram, Manohary ; Hurley, Katherine A. ; Foss, Marie H. ; Thornton, Kelsey M. ; Moore, Jared T. ; Shaw, Jared T. ; Weibel, Douglas B. / Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 6. pp. 1312-1319.
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