Aminocoumarin

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. [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] The Aminocoumarin antibiotics include

* Novobiocin, Albamycin (Pharmacia And Upjohn)
* Coumermycin
* Clorobiocin

tructure

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.

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. [Galm, Ute, Heller, Stefanie, Shapiro, Stuart, Page, Malcolm, Li, Shu-Ming, Heide, LutzAntimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis Antimicrob. "Agents Chemother". 2004 48: 1307–1312 ] They compete with ATPfor binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase.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.] X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of DNA gyrase.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] . Their affinity for gyrase is considerably higher than that of modern fluoroquinolones which also target DNA gyrase but at the gyrA subunit.Schmutz E, Mühlenweg A, Li SM, Heide L. (2003) Resistance genes of aminocoumarin producers: two type II topoisomerase genes confer resistance against coumermycin A1 and clorobiocin. "Antimicrob Agents Chemother." Mar;47(3):869-77.]

Resistance

Resistance to this class of antibiotics usually results from genetic mutation in the gyrB subunit. [M. Fujimoto-Nakamura, H. Ito, Y. Oyamada, T. Nishino, and J.-i. YamagishiAccumulation of Mutations in both gyrB and parE Genes Is Associated with High-Level Resistance to Novobiocin in Staphylococcus aureus"Antimicrob. Agents Chemother"., September 1, 2005; 49(9): 3810 - 3815.] Other mechanisms include de novo synthesis of a coumarin-resistant gyrase B subunit by the novobiocin producer "S. sphaeroides ".

Clinical use

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" [A. Maxwell, The interaction between coumarin drugs and DNA gyrase. "Mol. Microbiol". 9 (1993), pp. 681–686.] .

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