Antibiotic resistant bacteria represent one of the greatest current threats to human health on our planet. In the Third World, strains of tuberculosis bacteria are developing severe resistance against available antibiotics, causing a resurgence in this deadly disease. Current treatment for tuberculosis involves complicated, expensive and extensive, requiring a regimen of four different antibiotics taken every day for between four and six months. Compliance with such a regimen, especially in poor countries, is a serious problem. And even with full compliance, success rates with resistant tuberculosis strains are only about 70%. The problem is less severe in developed countries, but the treatment is still difficult and expensive.
Research aims to develop non-drug-resistant medications
Thus much current research is focused on developing drugs that are more effective against resistant strains of bacteria, and a new discovery is helping researchers better understand how the bacteria develop resistance to medications. As reported in the January 2013 issue of Science, researchers at the University of Tokyo and the Swiss Federal Institute of Technology made a surprising discovery that casts doubt on previously understood explanations of the drug resistance process.
The way antibiotics work is by attacking bacteria cells when the divide, and preventing them from building cell walls and thus completing their division process. A broadly accepted theory of antibiotic resistance is that some bacteria cells do not divide, and these cells are called persister cells. As they don’t divide, they are not susceptible to the antibiotics attacking the cell, and they "persist". Then, as more persister cells are created through the cells that do divide, the less effective the antibiotics are in treating the infection.
Previously understood drug resistance mechanisms may be incorrect
However, in a research project on a new possible tuberculosis medicine, the researchers discovered another phenomenon occurring instead of persistence. In a lab in Switzerland, the scientists tested a new front-line TB medicine known as isoniazid on a cousin of the TB bacterium, called Mycobacterium smegmatis. This bacterium is commonly used in research laboratories because it is safer than working with actual TB bacteria.
Isoniazid is part of a class of drugs known as "pro-drugs". These drugs do not take effect until they interact with certain chemicals inside the bacterial cell. When isoniazid interacts with an enzyme called KatG, the drug became activated. The researchers found that persistence did not affect the growth or reproduction rate of the bacterial cells at all. Instead, the cells randomly produced KatG in pulses, and between pulses there was no drug activity. Thus, bacterial cells that did not pulse KatG survived, and those that did, died.
"Pulsing is an infrequent and short-lived phenomenon, and most cells go from birth to next division without pulsing," said the Swiss institute's John McKinney, one of the lead authors.
Therefore, we could assume that if the drug were present with the bacterial cells for long enough, all the cells would eventually undergo a pulse of KatG and the infection would end.
"But remember, one of the unexpected findings in our study is that [persister] cells continue to grow and divide in the presence of antibiotics, which continuously replenishes the population," McKinney said. Those cells that survive would mutate resistance, he said.
No method to the madness
Unfortunately, the researchers could not find a pattern to the enzyme pulses, and it appears to be completely random, making it extremely difficult to target the phenomenon in any way.
To date, the researchers say it is unknown whether a similar pulse enzyme mechanism exists in other types of bacteria. They are even reluctant to push the idea, since in their experience, "…the persistence field has been held back by over-extrapolating the results from one system to other systems and I would rather not contribute to the muddle," says McKinney.
However, there are currently so few effective alternatives to available antibiotics, the issue is becoming urgent. These researchers just might have to push their new discovery a bit further in an effort to open new doors to new, effective antibiotics.