OBJECTIVES: Aminocoumarin antibiotics are potent inhibitors of bacterial DNA gyrase. We investigated the inhibitory and antibacterial activity of naturally occurring aminocoumarin antibiotics and six structural analogues (novclobiocins) against DNA gyrase and DNA topoisomerase IV from Escherichia coli and Staphylococcus aureus as well as the effect of potassium and sodium glutamate on the activity of these enzymes. METHODS: The inhibitory concentrations of the aminocoumarins were determined in gyrase supercoiling assays and topoisomerase IV decatenation assays. Both subunits of S. aureus topoisomerase IV were purified as His-Tag proteins in E. coli. The MIC was tested in vivo for the control organisms E. coli ATCC 25922 and S. aureus ATCC 29213. RESULTS: DNA gyrase is the primary target in vitro of all investigated aminocoumarins. With the exception of simocyclinone D8, all other aminocoumarins inhibited S. aureus gyrase on average 6-fold more effectively than E. coli gyrase. Potassium glutamate is essential for the activity of S. aureus gyrase and increases the sensitivity of E. coli gyrase to aminocoumarins ≥ 10-fold. The antibacterial activity of the tested compounds mirrored their relative activities against topoisomerases. CONCLUSIONS: The study provides insights about the substituents that are important for the inhibitory activity of aminocoumarins against the target enzymes, which will facilitate the rational design of improved antibiotics.
OBJECTIVES:Aminocoumarin antibiotics are potent inhibitors of bacterial DNA gyrase. We investigated the inhibitory and antibacterial activity of naturally occurring aminocoumarin antibiotics and six structural analogues (novclobiocins) against DNA gyrase and DNA topoisomerase IV from Escherichia coli and Staphylococcus aureus as well as the effect of potassium and sodium glutamate on the activity of these enzymes. METHODS: The inhibitory concentrations of the aminocoumarins were determined in gyrase supercoiling assays and topoisomerase IV decatenation assays. Both subunits of S. aureus topoisomerase IV were purified as His-Tag proteins in E. coli. The MIC was tested in vivo for the control organisms E. coli ATCC 25922 and S. aureus ATCC 29213. RESULTS: DNA gyrase is the primary target in vitro of all investigated aminocoumarins. With the exception of simocyclinone D8, all other aminocoumarins inhibited S. aureus gyrase on average 6-fold more effectively than E. coli gyrase. Potassium glutamate is essential for the activity of S. aureus gyrase and increases the sensitivity of E. coli gyrase to aminocoumarins ≥ 10-fold. The antibacterial activity of the tested compounds mirrored their relative activities against topoisomerases. CONCLUSIONS: The study provides insights about the substituents that are important for the inhibitory activity of aminocoumarins against the target enzymes, which will facilitate the rational design of improved antibiotics.
Authors: Jun Fan; Boudewijn L M de Jonge; Kathy MacCormack; Shubha Sriram; Robert E McLaughlin; Helen Plant; Marian Preston; Paul R Fleming; Robert Albert; Melinda Foulk; Scott D Mills Journal: Antimicrob Agents Chemother Date: 2014-09-22 Impact factor: 5.191
Authors: Tharindi D Panduwawala; Sarosh Iqbal; Amber L Thompson; Miroslav Genov; Alexander Pretsch; Dagmar Pretsch; Shuang Liu; Richard H Ebright; Alison Howells; Anthony Maxwell; Mark G Moloney Journal: Org Biomol Chem Date: 2019-06-05 Impact factor: 3.876
Authors: Katherine A Hurley; Thiago M A Santos; Molly R Fensterwald; Madhusudan Rajendran; Jared T Moore; Edward I Balmond; Brice J Blahnik; Katherine C Faulkner; Marie H Foss; Victoria A Heinrich; Matthew G Lammers; Lucas C Moore; Gregory D Reynolds; Galen P Shearn-Nance; Brian A Stearns; Zi W Yao; Jared T Shaw; Douglas B Weibel Journal: Medchemcomm Date: 2017-02-27 Impact factor: 3.597
Authors: Xiaoli Weng; Christopher H Bohrer; Kelsey Bettridge; Arvin Cesar Lagda; Cedric Cagliero; Ding Jun Jin; Jie Xiao Journal: Proc Natl Acad Sci U S A Date: 2019-09-16 Impact factor: 11.205