Aminocoumarin

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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,[1] whose best-known representative - Streptomyces coelicolor - was completely sequenced in 2002.[2] The Aminocoumarin antibiotics include:

Structure[edit]

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.[3]

Mechanism of action[edit]

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.[4] They compete with ATP for binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase.[5] X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of DNA gyrase.[3] Their affinity for gyrase is considerably higher than that of modern fluoroquinolones, which also target DNA gyrase but at the gyrA subunit.[6]

Resistance[edit]

Resistance to this class of antibiotics usually results from genetic mutation in the gyrB subunit.[7] Other mechanisms include de novo synthesis of a coumarin-resistant gyrase B subunit by the novobiocin producer S. sphaeroides .[6]

Clinical use[edit]

The clinical use of this antibiotic class has been restricted due to the low water solubility, low activity against gram-negative bacteria,[5] and toxiciy in vivo of this class of antibiotics.[8]

References[edit]

  1. ^ Heide, L. (2009). Chapter 18 AminocoumarinsMutasynthesis, Chemoenzymatic Synthesis, and Metabolic Engineering 459. pp. 437–455. doi:10.1016/S0076-6879(09)04618-7.  edit
  2. ^ 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
  3. ^ a b 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
  4. ^ 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
  5. ^ a b 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.
  6. ^ a b 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.
  7. ^ M. Fujimoto-Nakamura, H. Ito, Y. Oyamada, T. Nishino, and J.-i. Yamagishi Accumulation 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.
  8. ^ A. Maxwell, The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 9 (1993), pp. 681–686.