Computers Help Chemists Fight Emerging Infections

Newswise — Computer analysis of existing drugs may be key to fighting new infectious agents and antibiotic-resistant pathogens like deadly tuberculosis strains and staph 'superbugs.' Researchers in Canada say the use of such "emergency discovery" technology could save time, money and lives during a sudden outbreak or a bioterrorism attack. They reported here today at the 234th national meeting of the American Chemical Society.

Drug 'repurposing' or 'reprofiling' is not new: Pharmaceutical companies have been seeking new uses of old drugs to extend patent protections and whenever new, off-label uses of the drugs are found. But reprofiling to deliberately develop emergency drugs is a new concept, made possible by advances in chemoinformatics, a new field that merges chemistry with computer science, according to study presenter Artem Cherkasov, Ph.D., of the University of British Columbia in Vancouver, Canada.

"In the case of new infectious threats, there might be no time to develop a completely new drug 'from the ground up,' as the corresponding toxicological studies and regulatory investigations will take years to complete properly," says Cherkasov, a chemist with a background in computer-aided drug design and infectious disease. "Finding an already existing, well-studied therapeutic agent that will kill an emerging bug might provide a rapid, 'first line of defense' response option."

Under the new computer-aided system, the researchers plan to first identify vulnerable cellular components of a pathogen using proteomics, or the study of proteins and their interactions. They will enter these key structures into the computer and, using elements of modern 'Artificial Intelligence,' will identify drugs that have the highest potential for activity against the target and for antimicrobial activity, says Cherkasov. Those compounds with the highest 'ranking' can then be quickly tested in the laboratory against the pathogen and eventually used to treat infected individuals, the researcher says.

The new approach is still in development for possible future use during an actual outbreak, Cherkasov notes. However, many non-antibiotic drugs have been shown to have antibiotic-like properties using this technique, he says. For example, computer studies have suggested that lovastatin, a drug marketed to lower cholesterol, and gentisic acid, an anti-inflammatory drug related to aspirin, both show promise as strong antibiotics. But more studies are needed before these compounds can be recommended for use as antibiotics in a clinical setting, he adds.

"It is not totally unexpected as there are thousands of existing drugs that are already enriched with target-binding structural features," Cherkasov says. "Many of them were not designed as antibiotics but have the potential to act as such."

"The chemical structures of compounds we identify usually look nothing like known antibiotics. But if a compound behaves like antibiotic in a computational model, it may act as one in a real life," says Cherkasov, who has programmed his computer system to identify 'antibiotic likeness,' or those chemical structures which have the most potential for antibiotic activity.

There is a growing need to expand and complement the range of available antimicrobial compounds, as many big pharmaceutical companies have withdrawn from the field of anti-infective agents, according to Cherkasov. Only two novel antibiotics have entered the market in the last 20 years, he says.

The researchers plan to soon begin testing some of the newly identified antibiotic candidates against methicillin-resistant Staphylococcus aureus (MRSA). Also known as 'superbugs,' these bacteria are an increasingly worrisome cause of serious hospital-based infections and infections acquired in community settings.

Although Cherkasov's research team specializes in battling bacterial infections, similar techniques can be applied to emerging viral infections, such as SARS and bird flu, he says. Likewise, the technique also provides a potential means of identifying quick treatments for bioterrorism agents, such as new strains of anthrax, as well as rare infectious diseases such as those sometimes encountered in third-world countries.

Genome Canada, a funding and information resource of the Canadian government, supported the study as a part of the PREPARE project (PRoteomics for Emerging PAthogen Response), a non-government program based at the University of British Columbia.

The American Chemical Society — the world's largest scientific society — is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.

ALL PAPERS ARE EMBARGOED UNTIL DATE AND TIME OF PRESENTATION, UNLESS OTHERWISE NOTED

The paper on this research, CINF 016, will be presented at 2:50 PM, Sunday, 19 August 2007, during the symposium, "Drug Reprofiling."

CINF 016"Emergency discovery"; of novel antimicrobials among known drugs in response to new and reemerging infectious threats

Program Selection: Division of Chemical InformationTopic Selection: Drug Reprofiling

Abstract

Emergence of new infections is an increasing public health threat. The problem is that conventional antibiotic development is time-consuming, not very efficient and expensive. Moreover, current legal regulations require years of rigorous studies before a new antibiotic can enter the public sector. It becomes increasingly evident that such methodology doest not keep with emerging and re-emerging infections. As a partial but very rapid solution to this challenge we propose to identify established therapeutics with already approved toxicity and bioavailability properties that also exhibit sufficient activity against novel and re-emerging human pathogens. To assist such discoveries we have developed several QSAR approaches such as quantitative models of 'Antibiotic-likeness' and 'Bacterial-metabolite-likeness' enabling accurate recognition of antimicrobial substances from large collections of chemical structures. The developed models were able to relate several drugs from Merck database (with no antimicrobial annotation) to predicted antimicrobial action which has later been confirmed by other literature sources.

Researcher Provided Non-Technical Summary

Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public)

The main idea behind this research is simple. Say, there is a new infectious threat 'hitting' the general population (like recent outbreaks of SARS, Cryptococcus infection, hospital outbreaks of resistant pathogens etc), or there is a threat of bacteriological attack with old bugs (say, like Anthrax) or newly created deadly agents. We contemplate, that the one rapid and efficient way to address such threat would be to find a suitable, effective antagonist among already existing drugs.

In the case of new infectious threats there might be no time to develop a completely new drug 'from the ground up' as the corresponding toxicological, studies, regulatory investigations will take years to complete properly. But is there is already existing, approved, well-studied therapeutic agent which, as a useful side-effect, will kill the emerged bug (even though it wont be a complete cure) " that might be rapid, 'first-line defence' response option.

Given that there a thousands of known, approved drugs out there " there is always a good chance that we may be able to find suitable substance killing the emerged infectious agent (and there are examples when known, established but non-antibiotic drugs would be very efficient in eliminating infections). To find such candidates among thousands of known human therapeutics we will use computational approaches that help prioritizing the chemicals for their wet-lab experimental testing. That will further shorten the discovery time for such 'emergency antibiotic discovery'.

How new is this work and how does it differ from that of others who may be doing similar research?

There is a variety of on-going projects on re-profiling the existing drugs. I.e. scientists try to find other therapeutic applications (besides the main, originally-identified effect of the drug) for already existing medications. Usually, the main driving force for such discoveries is to expand the 'patent life span' of known drugs and/or to increase the profit.

I am not aware of any drug-reprofiling efforts resembling what we do with the "Emergency discovery" project.