By studying SQ109 for themselves, Oldfield's team determined that SQ109 does indeed block other proteins involved in critical functions in bacteria, fungi and parasites but not humans. They found it inhibits two enzymes that make the molecule menaquinone, which is involved in generating the cell's energy. Then they found that SQ109 had a third action, called uncoupling, which makes the cell membrane permeable essentially transforming the membrane from a wall to a screen door.
Then, the team created a dozen chemical analogs molecules that are structurally and functionally similar, but tweaked to be more effective or less toxic and tested them against cultures of bacteria, fungi, parasites and human cells. They found that they could make analogs with maximum effectiveness against certain classes of pathogens; for example, one analog turned out to be five times more potent against the tuberculosis bacterium than the original SQ109. They also found analogs that kill the parasites that cause the most serious and common form of malaria.
Now, the researchers are working with international collaborators to apply SQ109 analogs against other infectious diseases rampant in the tropical world, such as Chagas' disease, leishmaniasis and sleeping sickness.
Oldfield believes that multiple-target drugs, like SQ109 and its analogs, hold the key to antibiotic development in the age of drug resistance and the rise of so-called "superbugs." Evidence supports that assessment: So far, in experiments with tuberculosis, no instances of SQ109 resistance have been reported.
|Contact: Liz Ahlberg|
University of Illinois at Urbana-Champaign