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.^[1] The Aminocoumarin antibiotics include

Novobiocin, Albamycin® (Pharmacia And Upjohn)
Coumermycin
Clorobiocin

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.^[2] They compete with ATP for binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase.^[3] X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of DNA gyrase.^[4]

Structure

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.^[4]

Clinical use

The clinical use of these antibiotic class has been restricted due to their low water solubility, low activity against gram-negative bacteria^[3] and toxiciy in vivo^[5].

References

↑ 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.

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[1] 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

[2] 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

[M-3] 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.

[Tsai-4] 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

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

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Aminocoumarin

Mechanism of action

Structure

Clinical use

References

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