Web Date: May 20, 2013
Silencing Bacterial Communications
With the ever-growing specter of antibiotic resistance, scientists would like to develop new strategies and drugs to prevent bacterial infections. Now researchers have found potent new molecules that could keep staph infections at bay by disrupting how these cells communicate with each other to coordinate their pathogenic attacks (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja3112115).
Helen E. Blackwell of the University of Wisconsin, Madison, and her colleagues have been studying the chemical signals that bacteria use to sense how many other microbes of their kind are around, a phenomenon called quorum sensing. As the numbers of bacteria grow, so do the levels of the signaling molecules. These molecules activate receptors on the surfaces of the microbes. Once the molecules’ concentrations reach critical levels, the bacteria can change their behavior and act as a group to overwhelm the immune system of the host. Individual cells can’t do much on their own, Blackwell says. “They lie in wait until they reach that critical density.”
Messing with these bacterial communication pathways may lead to new antibacterial agents, says John K. McCormick of the University of Western Ontario, in Canada, who was not involved in the study. Because inhibitors of quorum sensing don’t kill the bacteria, they should be less likely to trigger bacterial resistance, he says.
In Staphylococcus aureus, cyclic peptides serve as quorum sensing signals. Although other researchers had tried blocking quorum sensing in the more common group I and II staph, Blackwell and her team chose to look at the group III bacteria that cause toxic shock syndrome, a possibly fatal form of infection.
The chemists changed individual amino acids within each peptide and examined how the substitutions affected the molecules’ ability to turn on the quorum sensing receptors. Based on this information, they determined which amino acids were important for the peptides’ activity.
For example, a simple modification in the original peptide structure, replacing an aspartate amino acid with an alanine, led to a very potent inhibitor. In biochemical tests with S. aureus, that compound was far more potent than others developed against quorum sensing in the species, and is active against all four strains of the bacteria, not just group III. At nanomolar concentrations, this peptide lowered the production of toxic shock syndrome toxin, which is regulated by quorum sensing pathways, in group III staph by 80%. That peptide also showed 40 times greater inhibition of quorum sensing than the previous best inhibitor against the more common group II strain.
Richard P. Novick of New York University Langone Medical Center calls the results “quite nice,” but cautions that the thiolactone linkages within the inhibitors are relatively unstable. With such instability, the compounds would break down in the body before they could effectively hit pathogens.
Blackwell and her colleagues are already working on more stable, simplified inhibitor structures that are easier to synthesize in large quantities. Eventually, they’d like to study the compounds in animal models of human infections.
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