New Type of Antibiotics Designed Not to Cause Resistance

If you work in infectious diseases in a hospital -- or frankly if you work anywhere in a hospital -- the emergence of antibiotic resistant bacteria is a serious problem. You have to be constantly aware of what the right drug is to prescribe to ensure its maximum effectiveness, and -- though rare -- there are some bacterial infections for which we have no good drugs.

This is why I was very intrigued about researchers trying to design antibiotics that would not create resistant bacteria:

Vern L. Schramm, Ph.D., professor and Ruth Merns Chair of Biochemistry at Einstein and senior author of the paper, hypothesized that antibiotics that could reduce the infective functions of bacteria, but not kill them, would minimize the risk that resistance would later develop.

Dr. Schramm's collaborators at Industrial Research Ltd. earlier reported transition state analogues of an enzyme that interferes with "quorum sensing" -- the process by which bacteria communicate with each other by producing and detecting signaling molecules known as autoinducers. These autoinducers coordinate bacterial gene expression and regulate processes -- including virulence -- that benefit the microbial community. Previous studies had shown that bacterial strains defective in quorum sensing cause less-serious infections.

Rather than killing Vibrio cholerae and E. coli 0157:H7, the researchers aimed to disrupt their ability to communicate via quorum sensing. Their target: A bacterial enzyme, MTAN, that is directly involved in synthesizing the autoinducers crucial to quorum sensing. Their plan: Design a substrate to which MTAN would bind much more tightly than to its natural substrate -- so tightly, in fact, that the substrate analog permanently "locks up" MTAN and inhibits it from fueling quorum sensing.

To design such a compound, the Schramm lab first formed a picture of an enzyme's transition state -- the brief (one-tenth of one-trillionth of a second) period in which a substrate is converted to a different chemical at an enzyme's catalytic site. (Dr. Schramm has pioneered efforts to synthesize transition state analogs that lock up enzymes of interest. One of these compounds, Forodesine, blocks an enzyme that triggers T-cell malignancies and is currently in a phase IIb pivitol clinical study treating cutaneous T-cell leukemia.)

In the Nature Chemical Biology study, Dr. Schramm and his colleagues tested three transition state analogs against the quorum sensing pathway. All three compounds were highly potent in disrupting quorum sensing in both V. cholerae and E. coli 0157:H7. To see whether the microbes would develop resistance, the researchers tested the analogs on 26 successive generations of both bacterial species. The 26th generations were as sensitive to the antibiotics as the first.

Basically, the idea here is to make antibiotics are that bacteriostatic rather than bacteriocidal. If the antibiotic doesn't kill the bacteria, their chances of becoming resistant to it by selection are much less. Further, you have plenty of non-resistant bacteria around to steal the nutrients of potentially resistant bacteria.

Quorum sensing -- when the bacteria communicate with one another through signaling molecules to generate group behavior -- is more important to bacteria that it initially sounds. Take the example of Pseudomonas aeruginosa. Pseudomonas is present in most unsterilized water. In hospital settings it can produce a real bastard of a pneumonia -- particularly in patients with cystic fibrosis, and it is super-resistant to many of our antibiotics. Pseudomonas uses quorum sensing to form biofilms. A biofilm is like bacteria goo that gets stuck to something. In some cases, you can get biofilms of Pseudomonas over an infected valve in your heart. The bummer with biofilms is that you can bombard them with antibiotics and kill a lot of the surface bacteria, but the ones on the inside of the film will survive. So interfering with quorum sensing, even though it may not kill the bacteria outright, would certainly make some of them easier to fight.

I do have a couple questions about antibiotics designed not to cause resistance.

First, I wonder whether resistance would still be theoretically possible even when the antibiotics do not kill the bacteria. Consider a situation where a subset of the bacteria -- due to a mutation -- can quorum sense even in the presence of the drug. Now, they might still have a reproductive advantage over the other bacteria in your system -- maybe because they can still form biofilms which leads to more of them. This advantage may lead to an increase in their relative proportion in the system. It would still be true that non-resistant bacteria would be in the way of that strain becoming totally dominant. Thus, I would totally believe that resistance would form much more slowly to these agents. But I am dubious that it could never develop.

Second, a lot of the problem that we have with resistant strains in hospital settings is treating immunocompromised patients. HIV+ patients get a lot of infections. The idea with these bacteriostatic agents is to allow the immune system to get a foot hold over the infection, but that won't work in someone who has little functional immune system left. Therefore, the use of bacteriostatic agents would probably be circumscribed in these patients, or they would have to be combined with bacteriocidal compounds.

Still, some really interesting stuff in antibiotic research.