home   genetic news   bioinformatics   biotechnology   literature   journals   ethics   positions   events   sitemap
  HUM-MOLGEN -> Genetic News | search  

Drug-Resistant Bacteria May Find New Foe In Novel Drug Design Approach

  August, 30 2004 12:58
your information resource in human molecular genetics
PHILADELPHIA, PA-August 25, 2004--At the 228th national meeting of the American Chemical Society held this week in Philadelphia, researchers from Harvard Medical School report that they have found a way to produce novel aminocoumarins – antibiotics that can help in the fight against drug-resistant bacteria.

The development of bacterial resistance to antibiotics is a major public health concern. Currently, doctors have precious few weapons to fight strains such as methicillin-resistant Staphylococcus aureus (MRSA). Though some of these “super bugs” are sensitive to aminocoumarins, there’s a catch. Low solubility, poor absorption and distribution, and the inability to penetrate the bacterial cell wall, make these compounds less than ideal antibiotics.

Now, Christopher T. Walsh, the Hamilton Kuhn Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, and colleagues report a method that can be used to generate potentially hundreds of aminocoumarin variants. “This approach allows the controlled variation of all parts of the aminocoumarin scaffold in the search to create antibiotics with tailored and improved properties,” said Walsh.

In an ironic twist, the method developed by the researchers exploits bacterial enzymes. Caren Freel Meyers, a research fellow in Walsh’s lab, has used an alphabet soup of proteins from Streptomyces to make an enzymatic production line that adds, stepwise, different chemical moieties to the backbone of coumermycin A1, a member of the aminocoumarin family of antibiotics.

Starting with this coumermycin scaffold, Freel Meyers used the enzyme CouL to add one or two amino groups, then CouM to add a sugar component called L-noviose. The enzyme CouP was found to add methyl groups to the CouM products, and NovN was used to add one or two carbamoyl moieties to methylated CouP product variants. By playing mix-and-match with enzymes and CouL substrates that make up the coumermycin A1 backbone, multiple designs can be rolled off the production line. In a proof of principle experiment, Freel Meyers generated a library of nine coumermycin variants. Three of these compounds have been produced in sufficient quantity for detailed analysis, and they are currently undergoing biological evaluation.

Aminocoumarins are inhibitors of bacterial type II topoisomerases, enzymes that untwist and unknot DNA. Without these topoisomerases bacteria cannot replicate. For this reason, fluoroquinolone antibiotics, such as ciprofloxacin and levofloxacin, which are potent inhibitors of type II topoisomerases, have found widespread use. However, the emergence of resistant bacterial strains has renewed interest in the aminocoumarin novobiocin, which is one of the few drugs available that is effective against MRSA.

The sugar moieties attached to the coumermycin backbone are thought to bind to and inactivate the essential bacterial topoisomerase DNA gyrase. By modifying the noviose substituents Freel Meyers and colleagues hope to develop more effective gyrase inhibitors. By modifying other components of the backbone the researchers hope to turn these inhibitors into potent antibiotics, ones that are more soluble, have better pharmacokinetics, and more readily penetrate their bacterial targets.

(C) 2004 - Harvard Medical School

Message posted by: Frank S. Zollmann

print this article mail this article
Latest News
Variants Associated with Pediatric Allergic Disorder

Mutations in PHF6 Found in T-Cell Leukemia

Genetic Risk Variant for Urinary Bladder Cancer

Antibody Has Therapeutic Effect on Mice with ALS

Regulating P53 Activity in Cancer Cells

Anti-RNA Therapy Counters Breast Cancer Spread

Mitochondrial DNA Diversity

The Power of RNA Sequencing

‘Pro-Ageing' Therapy for Cancer?

Niche Genetics Influence Leukaemia

Molecular Biology: Clinical Promise for RNA Interference

Chemoprevention Cocktail for Colon Cancer

more news ...

Generated by News Editor 2.0 by Kai Garlipp
WWW: Kai Garlipp, Frank S. Zollmann.
7.0 © 1995-2023 HUM-MOLGEN. All rights reserved. Liability, Copyright and Imprint.