BioWorld International Correspondent
LONDON - Insights into how a common antibacterial agent forms a cage around a key component of bacterial cell walls could help pharmacologists design new antibiotics to replace those no longer effective.
Researchers working in the Netherlands have shown how nisin, which has been used for decades as a food preservative, binds lipid II (used by bacteria to synthesize their cell walls).
Robert Kaptein, professor of chemistry at Utrecht University, told BioWorld International: "We have identified a novel 3-dimensional structure of the complex between nisin and lipid II. The binding involved is different to that of all other antibiotics. We hope that this information will help suggest the design of novel antibiotics."
The work is reported in the Sept. 12, 2004, issue of Nature Structural and Molecular Biology in a paper titled "The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics."
Nisin is used in Europe and the U.S. to preserve dairy products and beer. It is an antibacterial peptide produced by the bacterium Lactococcus lactis. It is classified as a lanthionine-containing antibiotic, or lantibiotic, because it contains chemical entities called lanthionine bridges.
Nisin is not toxic to humans, and there have been no reports of resistance to nisin. However, despite such desirable features, nisin is not suitable for use as a clinical antibiotic because of the difficulty of delivering it to the body in suitable concentrations.
Researchers, therefore, have probed the secrets of its action in the hope of being able to design compounds that mimic it, but that will have improved pharmacokinetic characteristics.
In late 1999, Eefjan Breukink at the Center of Biomembranes and Lipid Enzymology in Utrecht and colleagues reported in Science that nisin uses lipid II to form pores in bacterial cell walls, and that that was the antibiotic's sole target.
Breukink, who also is an author of the paper, told BioWorld International at that time that they wanted to learn which parts of nisin interact with lipid II, saying that "if we can find out what is needed to bind lipid II with high affinity and form a pore in the membrane, then you are in business to get high-affinity antibiotics."
The latest paper describes the results of some of the past four years' work. Kaptein, Breukink and colleagues used nuclear magnetic resonance spectroscopy to study the complex made by nisin and lipid II in solution.
Kaptein said: "We found that the lanthionine rings that are conserved in several lipid II-binding lantibiotics recognize and bind to the pyrophosphate moiety of lipid II. This suggests why these ring structures exist, and why these rings are always conserved in members of this family of compounds that retain antibacterial activity."
The pyrophosphate "cage," he added, is a new structural motif. Vancomycin also binds to lipid II, but does so in a different way.
As Kaptein and his colleagues point out in the Nature Structural and Molecular Biology paper, bacteria that are resistant to vancomycin, which have the vanA-type gene cluster, have replaced the amino acids at one end of the lipid II molecule with a slightly different sequence. Yet nisin remains active against such resistant bacteria, demonstrating that its method of binding to lipid II is different.
The authors concluded that the pyrophosphate moiety of lipid II "is the Achilles' heel of bacteria that cannot be altered or replaced by simple mutations as opposed to alteration of the attached pentapeptide that can lead to vancomycin resistance."
The team's research plan includes finding out whether other lantibiotics bind to lipid II in the same way. They also want to study how nisin forms pores in the bacterial membrane - a process that involves larger assemblies of the complexes between nisin and lipid II.
"In addition, since we now know what the main interactions are, and where the hydrogen bonds need to be made, we want to find out if we can emulate this binding with a peptide or other analogue molecules - and we hope that such a molecule may have better properties for acting as a drug," Kaptein said.