Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology.
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.
Department of Biochemistry, ‡Department of Pharmaceutical Sciences, and ∥Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
Manohary
M
Rajendram
Katherine A
KA
Hurley
Marie H
MH
Foss
Kelsey M
KM
Thornton
Jared T
JT
Moore
Jared T
JT
Shaw
Douglas B
DB
Weibel
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002876:Chromosomes, Bacterial / Q000235:genetics*; D027081:DNA Gyrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004269:DNA, Bacterial / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D005434:Flow Cytometry; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D011759:Pyrrolidines; D059005:Topoisomerase II Inhibitors; C000600627:gyramide A; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D027081:DNA Gyrase