Aminocoumarin

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.

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, Lutz Antimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis Antimicrob. Agents Chemother. 2004 48: 1307–1312 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. Their affinity for gyrase is considerably higher than that of modern fluoroquinolones, which also target DNA gyrase but at the gyrA subunit.

Resistance

Resistance to this class of antibiotics usually results from genetic mutation in the gyrB subunit. 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 this antibiotic class has been restricted due to the low water solubility, low activity against gram-negative bacteria,

References

References

1. (2002). "Complete genome sequence of the model actinomycete "Streptomyces coelicolor" A3(2)". Nature.
2. (2003). "The ATP-binding site of type II topoisomerases as a target for antibacterial drugs". Curr Top Med Chem.
3. (1997). "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.
4. (2003). "Resistance genes of aminocoumarin producers: two type II topoisomerase genes confer resistance against coumermycin A1 and clorobiocin". Antimicrob Agents Chemother.
5. (2005). "Accumulation of Mutations in both gyrB and parE Genes Is Associated with High-Level Resistance to Novobiocin in Staphylococcus aureus". Antimicrob. Agents Chemother..
6. and toxicity ''in vivo'' of this class of antibiotics.A. Maxwell, The interaction between coumarin drugs and DNA gyrase. ''Mol. Microbiol''. 9 (1993), pp. 681–686.