Aminocoumarin is a class of antibiotics that act by an inhibition of the DNA gyrase enzyme involved in the cell division in bacteria. They are derived from Streptomyces species, whose best-known representative – Streptomyces coelicolor – was completely sequenced in 2002. The aminocoumarin antibiotics include:
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. 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 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 .
- Heide, L. (2009). "Chapter 18 AminocoumarinsMutasynthesis, Chemoenzymatic Synthesis, and Metabolic Engineering". Methods Enzymol. Methods in Enzymology. 459: 437–455. doi:10.1016/S0076-6879(09)04618-7. ISBN 9780123745910. PMID 19362650.
- Bentley, SD; et al. (2002). "Complete genome sequence of the model actinomycete "Streptomyces coelicolor" A3(2)". Nature. 417 (6885): 141–147. doi:10.1038/417141a. PMID 12000953. S2CID 4430218.
- Sonia Ilaria Maffioli (2014). "A Chemist's Survey of Different Antibiotic Classes". In Claudio O. Gualerzi; Letizia Brandi; Attilio Fabbretti; Cynthia L. Pon. (eds.). Antibiotics: Targets, Mechanisms and Resistance. Wiley-VCH. ISBN 9783527659685.
- Tsai, F.T.F.; Singh, O.M.; Wonacott, A.J.; Weston, S.; Tucker, A.; Pauptit, R.A.; Breeze, A.L.; Poyser, J.P.; O'Brien, R.; et al. (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. 28 (1): 41–52. doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-b. PMID 9144789.
- 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
- Maxwell, A.; Lawson, D. M. (2003). "The ATP-binding site of type II topoisomerases as a target for antibacterial drugs". Curr Top Med Chem. 3 (3): 283–303. doi:10.2174/1568026033452500. PMID 12570764.
- 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. 47 (3): 869–77. doi:10.1128/aac.47.3.869-877.2003. PMC 149333. PMID 12604514.
- Fujimoto-Nakamura, M.; Ito, H.; Oyamada, Y.; Nishino, T.; Yamagishi, J.-I. (2005). "Accumulation of Mutations in both gyrB and parE Genes Is Associated with High-Level Resistance to Novobiocin in Staphylococcus aureus". Antimicrob. Agents Chemother. 49 (9): 3810–3815. doi:10.1128/aac.49.9.3810-3815.2005. PMC 1195401. PMID 16127057.
- A. Maxwell, The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 9 (1993), pp. 681–686.