Evolvability -a factor in drug resistance?

Related tags Antibiotic resistance Us food and drug administration

Scientists may be fighting a losing battle to develop alternative
treatments to drug resistant pathogens, as research reveals the
evolution of drug resistance in bacteria is a trait that is
favoured through the process of natural selection.

The discovery represents problems for the pharmaceutical industry, which already face a number of key challenges, in particular a reduction in the useful lifespan of antibacterial products.

The threat of hospital infections such as vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) and its spread into the general community comes at a time when pharmaceutical companies are reining back their spending on new anti-infectives.

Concerns over pathogen resistance are causing a general curb on usage, and the increasing prevalence of resistance has prompted official regulators to place greater demands on manufacturers. For example, approval of Aventis' ketolide antibiotic Ketek (telithromycin) was held up by the US Food and Drug Administration for several months by requests for additional data on resistant strains.

Researchers Michael Deem and David Earl based their conclusions from a computer simulation that recorded protein mutation based on external environmental changes. As frequency and severity of environmental changes varied there was increased likelihood of survival among proteins that mutated more frequently.

Deem told DrugResearcher.com:"Drugs provide a selective pressure for the disease-causing organism to evolve, circumventing the drug effect. Whenever the environment fluctuates, the potential for escape from the drug becomes dramatically higher."

"For infectious disease, the pressure can be fluctuating as some of the infected people are treated. Or the fluctuations can occur because different drugs are used in different people. Diseases for which increased disease evolution of drug resistance is a problem include influenza, gonorrhoea, HIV and cancer."

In HIV-1 protease, mutation is not randomly distributed within the structure but concentrated at sites that alter the geometry of the protein-binding domain, conferring significant propensity for antigenic drift. This action has widespread implications for drug design and the evolution of drug resistance.

Deem commented: "These ideas and simulation results are generally valuable to fundamental drug design efforts. They are also valuable in the construction of treatment protocols which drugs to use, for what people, and how."

"Whenever there is a decision to be made, such as what is the best target, these evolutionary considerations can be part of the science that shapes the answer. For example, there is currently consideration of how likely a drug binding site is to mutate by point mutations in drug design efforts."

The two scientists argue that wide variation among bacteria and other antigens has put selective pressure on our immune systems to rapidly adapt methods of identifying and attacking invaders. Similar observations on the rapid mutability among flu viruses and other invading pathogens provide additional evidence, they said.

Earl said: "At the level of treatment protocols, the theory provides a general insight into how drug resistance can be slowed or speed up. For example, the result that cycling of drugs in a hospital is likely to be lead to increased resistance is naturally understood with this paradigm. Also, the result that incomplete treatments for turburculosis lead to a more rapid evolution of drug resistance tuburculosis is also naturally understood."

"So, all else being equal, treatments that are uniformly suppressing the infectious agent are better than treatments that vary the degree of suppression in a person or in a population."

The annual cost for treating antibiotic resistant infections is approximately $30 billion (€25.7bn) in the USA alone, with the most common pathogens starting to elude last-line antibiotic therapies.

The results of the study appear in the August 10 issue of Proceedings of the National Academy of Sciences.

Related topics Preclinical Research Ingredients

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