Professor of Microbiology and Medicine
Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine
Dr. Richard P. Novick began studying Staphylococcus aureus 45 years ago, long before drug-resistant strains became the hospital scourge they are today. While others are working on the problem of resistance, Dr. Novick's lab is investigating how the bacterium controls expression of its genes for virulence (ability to cause infection). He and his colleagues have uncovered an accessory gene regulation system (Agr) that is the major governor of virulence. They have identified among its components an autoinducing peptide (AIP) and its receptor, (AgrC), which initiate the activation circuit. This work may eventually lead to a way of breaking the circuit—in effect, disarming S. aureus until the host immune system can knock it out. In a recent study published in the Journal of Biological Chemistry, Dr. Novick and his colleagues further elucidate how virulence genes are controlled in the bacterium.
Q. You have zeroed in on a specific accessory gene regulator, AgrC, which you refer to as a quorum-sensing receptor. Isn't a quorum the number of individuals needed to start a meeting?
A. Exactly. There are certain bacterial metabolic processes that function only at a certain population density. It depends on the number of bacteria and the space in which they are confined. The bacteria that do this secrete a substance known as an autoinducer because it activates its own synthesis. At the same time, it activates the gene regulatory system, which is dependent on the concentration of this substance. More and more of the autoinducer is made until all of a sudden it takes off, more or less exponentially, and creates a huge explosion of gene products. Our staphylococci [S. aureus] produce a quorum-sensing autoinducing peptide that regulates the entire set of virulence genes in the organism. We are studying this AIP and its interaction with a receptor protein (AgrC) to turn on the gene regulatory system.
Q. You are engaged in ongoing studies to understand how S. aureus works to cause infection. What knowledge were you building on and what were you trying to find out in this particular study?
A. We've spent many, many years characterizing this whole autoinduction system, as we call it, finding out which genes it regulates and how it regulates them. The biology has a number of interesting features. A very important one is that staphylococci have developed variations in the sequence of this peptide and receptor such that the peptide that is produced by one variant will inhibit activation in the others and vice versa. Only the one that is made by the producing organism can activate its own regulatory system. It's a very interesting biochemical problem, which we don't understand exactly. In this study, we were trying to find out how the receptor distinguishes which peptide is coming along. And we were attempting to define the region on the receptor protein that is required for interaction with the peptide.
Q. Did you get the answers?
A. Not entirely. We used two AIPs, called type I and type IV, produced by two different sets of staphylococci, which we call Agr groups I and IV. These AIPs differ by only a single amino acid so we could switch them back and forth. We found that their receptors were so closely related that both AIPs have activity against both receptors, but at very different levels, so it's not a total distinction between the two, just a partial distinction. We also found out which amino acids on the receptor are responsible for being activated.
Q. What is the next step?
A. The next step is to look at other AIPs—groups II and III—to see if we can figure out which amino acids on their receptors determine recognition. We're doing that now. These two AIP/agr groups have much larger differences, so it's much harder to attack the problem directly.
Q. Does this work have wider implications? Could it shed light on how virulence works in other organisms?
A. We do not expect the staphylococcal peptides to interact with any other species, but it turns out that this system is very widely distributed among bacteria. However, in only a very small number has it been shown to do anything, so that's a wide area that is open for investigation. The only other organism for which there's been significant data that implicates it in virulence is Enterococcus, whose AIP is significantly different from the staphylococcal ones.
Q. Are there potential clinical applications for your work with the S. aureus autoinduction system?
A. If you block the expression of these genes, the organism is much easier game for the host immune system. Blocking it doesn't totally wipe out the ability of the staphylococci to cause infection, but it will keep the organism in check long enough for the host to mobilize its defenses. This approach hasn't been tried in a clinical situation. We have observed that a naturally occurring mutant form of staphylococcus that cannot use this system to express its virulence genes causes pneumonia infections that are considerably less serious. Although I don’t imagine that Agr-inhibiting peptides will ever be a standalone therapy, I can certainly imagine it being used in conjunction with antibiotics.