Kishony work on combinations of drugs began in 2006 when his laboratory has shown that to understand why some drugs work well or poorly together can help researchers identify the cellular functions they attack. For example, drugs that block protein production work badly with drugs that block DNA replication, but they work well with drugs that weaken the cell wall.To confirm these initial findings, the team conducted a second series of experiments which have compromised the ability of E. coli for the production of ribosomes. As a result, the cells can more easily withstand the assault of the first drug, yet succumbed to the second, completely eliminating the strong antagonism between the drugs.
Drugs that inhibit DNA synthesis, such as ciprofloxacin , interrupt cell division. As a result, E. coli into a state of stress.
However, since the Kishony lab discovered in 2008 that the antagonistic pairs of drugs slow the progression of antibiotic resistance has become increasingly clear that these drug combinations warrant further studies.
The work was done in collaboration with Stanford University research associate Selwyn Quan, is described in his cell on November 13.
When the team has added additional stress to inhibit protein synthesis of drugs such as tetracycline, instead of causing the death of more cells, the second drug to overproduction of ribosomes and proteins. Since this drug inhibits the rest of the ribosome, it corrects for the fact that the cell has too many in the first place, said Bollenbach.
This research was funded by the National Institutes of Health. Bollenbach received support from a scholarship from the Alexander von Humboldt.
But with ciprofloxacin, the cells try to repair DNA, while the production of ribosomes. It is not in the best interest of the cell, because making ribosomes uses resources and creates a surplus of cellular proteins, which is even more expensive.
Understanding how cells change their genetic programs in the presence of antibiotics can provide guidance on ways to discourage the growth of pathogens and promote the growth of good bacteria in the laboratory and clinic, said Kishony.
Just as some drugs work better together, however, other pairs are counter-productive. The question we asked was how is it possible that two drugs in combination are less effective than a single one of them, said the lead author and professor at Harvard Medical School associate of systems biology Roy Kishony.
According to the first author and researcher in systems biology Tobias Bollenbach, clinical researchers are primarily interested in drugs that together work better than one, and if the studies tend to focus on to explain some mechanisms of the synergistic drug pairs originally.
Identify Wnt16 as a key factor in the production of HSC significantly expands what is known about how HSCs are formed and provides insight into new tissues talk to each other to achieve the ultimate goal to produce the adult blood system. We’re going to figure out something that people have been asking for decades, said Wilson K. Clements, lead author of the study and a postdoctoral fellow in the laboratory of Traver.
The work suggests that there are things about antibiotics and other inhibitors that we never suspected, said the University of British Columbia microbiologist Julian Davies, We are so naive about how drugs work. We are so naive about the activities of these compounds once they are actually human beings. I think it will be important this work is that people will be able to design model studies with animals.
The discovery has inspired Kishony and his team to ask a broader question of antibiotic interactions.
Kishony recently received a grant of federal stimulus to pursue a study that explores the genetic determinants of drug interactions and broader attempts to determine whether the cells can be synthetically manipulated to change the way the drugs interact.