Aminocoumarin is a class of antibiotics which act by an inhibition of the DNA Gyrase enzyme involved in the cell division in bacteria. They are derived from Streptomyces species, whose most well-known representative Streptomyces coelicolor was completely sequenced in 2002. The Aminocoumarin antibiotics include
- Novobiocin, Albamycin® (Pharmacia And Upjohn)
Mechanism of action
The Aminocoumarin antibiotics are known inhibitors of DNA gyrase. Antibiotics of the aminocoumarin family exert their therapeutic activity by binding tightly to the B subunit of bacterial DNA gyrase, thereby inhibiting this essential enzyme. They compete with ATP for binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase. X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of DNA gyrase.
The core of aminocoumarin antibiotics is made up of a 3-Amino-4,7-dihydroxycumarin ring, which is linked e.g. with a sugar in 7-Position and a benzoic acid derivative in 3-Position.
Clorobiocin is a natural antibiotic isolated from several Streptomyces strains and differs from novobiocin in that the methyl group at the 8 position in the coumarin ring of novobiocin is replaced by a chlorine atom, and the carbamoyl at the 3' position of the noviose sugar is substituted by a 5-methyl-2-pyrrolylcarbonyl group.
The clinical use of these antibiotic class has been restricted due to their low water solubility, low activity against gram-negative bacteria and toxiciy in vivo.
- ↑ Bentley SD, et al. Complete genome sequence of the model actinomycete "Streptomyces coelicolor" A3(2). Nature. 2002 (417)141–147 http://www.nature.com/nature/journal/v417/n6885/abs/417141a.html
- ↑ Galm, Ute, Heller, Stefanie, Shapiro, Stuart, Page, Malcolm, Li, Shu-Ming, Heide, Lutz Antimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis Antimicrob. Agents Chemother. 2004 48: 1307-1312
- ↑ 3.0 3.1 Maxwell, A., and Lawson, D. M. (2003). The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr Top Med Chem, 3, 283-303.
- ↑ 4.0 4.1 F.T.F. Tsai, O.M. Singh, T.Skarzynski, A.J. Wonacott, S. Weston, A. Tucker, R.A. Pauptit, A.L. Breeze, J.P. Poyser, R. O'Brien et al., The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins 28 (1997), pp. 41–52
- ↑ A. Maxwell, The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 9 (1993), pp. 681–686.