By Tyler Irving
Posted July 2011
Pharmacists are constantly warning us to avoid mixing medications because of the risk of harmful interactions. But a team at McMaster University recently demonstrated that when it comes to antibiotics, interactions with other medications can sometimes be beneficial.
Until now, rational drug design has largely focused on disrupting the genetic pathways of pathogens that are known to be essential for life. For example, in the case of E. coli, only about 300 of the approximately 4,500 genes are essential. “All the drug companies, in the late 1990s and early 2000s, went after those hammer and tongs and the net result has been no new drugs,” says Gerry Wright, scientific director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University. That’s because many of those pathways are hard to disrupt with drugs and those that aren’t often have analogues in human cells. Wright and the research team suspected that they might get better results by targeting multiple non-essential pathways rather than a single essential one.
To do this, the team drew up a list of 1,057 off-patent drugs that are known to be bioactive but not necessarily against pathogens. They tested each of these drugs, combining them with the antibiotic minocycline and determining the effect on the disease-causing organisms E. coli, S. aureus and P. aeruginosa. To their surprise, 69 of these combinations showed a synergistic effect. One of these was loperamide, which is marketed as Imodium. The team selected this for an in vivo validation using a mouse model of Salmonella infection. Sure enough, the loperamide-minocycline combination performed better than either drug by itself.
Wright is encouraged by this finding. “We’re looking at other antibiotics and other compound libraries and we’re identifying a whole bunch of new, completely unexpected partners.” The work was published in last month’s issue of Nature Chemical Biology.
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