Putting bacterial antibiotic resistance into reverse

April 25, 2010, Federation of American Societies for Experimental Biology

The use of antibiotics to treat bacterial infections causes a continual and vicious cycle in which antibiotic treatment leads to the emergence and spread of resistant strains, forcing the use of additional drugs leading to further multi-drug resistance.

But what if it doesn't have to be that way?

In a presentation at the American Society for Biochemistry and Molecular Biology's annual meeting, titled "Driving backwards the evolution of antibiotic resistance," Harvard researcher Roy Kishony will discuss his recent work showing that some drug combinations can stop or even reverse the normal trend, favoring bacteria that do not develop resistance. The talk will be in Anaheim Convention Center Room 304D, on Sunday April 25 at 3:30 pm PST.

"Normally, when clinicians administer a multi-drug regimen, they do so because the drugs act synergistically and speed up bacterial killing," Kishony explains. However, Kishony's laboratory has focused on the opposite phenomenon: antibiotic interactions that have a suppressive effect, namely when the combined of using the two drugs together is weaker than that of one of the drugs alone.

Kishony and his team identified the suppressive interaction in E. coli, discovering that a combination of tetracycline - which prevents bacteria from making proteins - and ciprofloxacin - which prevents them from copying their DNA - was not as good as slowing down as one of the antibiotics (ciprofloxacin) by itself.

Kishony notes that this suppressive interaction can halt bacterial evolution, because any bacteria that develop a resistance to tetracycline will lose its suppressive effect against ciprofloxacin and die off; therefore, in a population the bacteria that remain non-resistant become the dominant strain.

While such a weakened antibiotic combination is not great from a clinical standpoint, the Kishony lab is using this discovery to set up a system that could identify novel drug combinations that could hinder the development of resistance but still act highly effectively.

"Typical drug searches look for absolute killing effects, and choose the strongest candidates," he says. "Our approach is going to ask how these drugs affect the competition between resistant versus sensitive bacterial strains."

To develop such a screen, Kishony and his group first had to figure how this unusual interaction works.

"Fast growing bacteria like E. coli are optimized to balance their protein and DNA activity to grow and divide as quickly as the surrounding environment allows," Kishony explains. "However, when we exposed E. coli to the ciprofloxacin, we found that their optimization disappeared."

"We expected that since the bacteria would have more difficulty copying DNA, they would slow down their protein synthesis, too," Kishony continues. "But they didn't; they kept churning out proteins, which only added to their stress." However, once they added the tetracycline and protein synthesis was also reduced in the E. coli, they actually grew better than before. They then confirmed the idea that production of ribosomes - the cell components that make proteins - is too high under DNA stress by engineering E. coli strains that have fewer ribosomes than regular . While these mutants grew a more slowly in normal conditions, they grew faster under inhibition of DNA synthesis.

Kishony notes that their preliminary work on the development of a screen for drugs that put resistance in a disadvantage looks promising, and hopes that it would lead to the identification of novel drugs that select against resistance.

Related Stories

Recommended for you

Anemia discovery offers new targets to treat fatigue in millions

January 22, 2018
A new discovery from the University of Virginia School of Medicine has revealed an unknown clockwork mechanism within the body that controls the creation of oxygen-carrying red blood cells. The finding sheds light on iron-restricted ...

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.