Angewandte Chemie International Edition
© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2004, 43 (48), 6734—6738
Killing Resistant Germs
Paromomycin derivative as a potential drug against multiple-resistant Staphylococci
To fend off a bacterial infection, there are a number of points of attack in the metabolism of invaders. The antibiotic paromomycin, an aminoglycoside (a compound made of nitrogen-containing sugar components), drives up the error rate in protein biosynthesis, stopping the multiplication of the bacteria. Unfortunately, aside from the risk of severe side effects, this class of antibiotic has another disadvantage: The drugs are easily deactivated by special enzymes that can be produced by resistant strains of bacteria. A Canadian, French, and American research team has now developed a novel paromomycin derivative that may be a potential starting point for the next generation of aminoglycoside antibiotics.
To produce a protein, cells make a copy of the DNA segment that codes for the protein in question. The copy consists of an RNA strand, which then acts as "assembly instructions" once it is "deposited" in the cellular protein synthesis apparatus, the ribosome. The instructions are decoded at the A binding site of the ribosome. Here, "adapter"-RNA molecules, which have one end that fits precisely onto the most recently read codon of the assembly instructions, are docked. At the other end of each adapter is the amino acid that corresponds to this codon. The acid is then attached to the end of the growing protein chain. The crucial A binding site is where paromomycin, a molecule made of four rings, hooks on, affecting the precision of the copying process.
An additional side chain could improve the binding of the drug to the ribosome, thought the research team headed by Stephen Hanessian (University of Montreal, Canada), Eric Westhof (Université Louis Pasteur, France) as well as Ibis Therapeutics (U.S.A.). An OH group on ring III was identified as a suitable point of attachment. As the researchers hoped, one of the analogues produced in this manner proved particularly effective, even taking on a multiply resistant strain of staphylococcus that vanquishes conventional aminoglycosides. The new side-chain in this analog presumably is not recognized by inactivating bacterial enzymes.
An X-ray analysis uncovered something astonishing: a novel mode of binding between the A binding site and the drug. Whereas rings I and II are bound in the furrow of the A binding site almost identically to paromomycin, ring III is twisted by 40° and folded in on itself differently from the equivalent ring of paromomycin. This causes ring IV to lie in a position that is different by 90°. The new orientation results in additional bonds between rings II and IV and the A binding site of the ribosome. The new side chain itself, on the other hand, barely forms any new contacts to the A binding site.