New route to identify drugs that can fight bacterial infections
A handful of drugs on the list inhibit the growth of at least three of the four bacterial organisms tested. Those drugs include familiar compounds like loperamide, an antidiarrheal medication sold under the brand name Imodium® and clemastine, an allergy medicine sold as Tavist®, as well as drugs used to treat high blood pressure and angina.
"Antibiotic therapy is becoming more difficult to achieve, so looking for alternatives is always a good thing to do," Shuman says.
Shuman and his colleagues thought that certain types of bacteria-those that infect human cells and then replicate inside those cells-might be vulnerable to other drug approaches.
"Intracellular bacteria resemble viruses in that they need host cell functions to complete their life cycle," says Shuman. So the researchers screened drugs to look for compounds that interfered with those cellular processes. They chose a panel of 640
The researchers measured each drug's ability to disrupt the intracellular growth of four bacterial strains: Coxiella burnetii (which causes Q fever), Legionella pneumophila (Legionnaires' disease), Brucella abortus (brucellosis), and Rickettsia conorii (Mediterranean spotted fever). Although none of these organisms have become problem infections in the U.S. due to antibiotic resistance, brucellosis and Q fever can both cause chronic and ultimately fatal disease in about 5% of those infected.
The team screened each drug for its ability to reduce intracellular bacterial growth by 80% or more inside human THP-1 macrophage-like immune cells. They eliminated drugs from the list that simply killed off the human host cells or that were known antibiotic or antiviral drugs and identified 101 drugs that presumably disrupt key cellular functions in the host cells.
Shuman's lab group did the experiments on C. brunetii and L. pneumophila, while
"There are emerging infections of all sorts-bacteria, viruses, parasites. Working up a new therapy for such things take time," says Shuman. "If we have drugs X, Y, or Z to interfere with host cell functions to slow or impede an infection, then we can have something already on hand to attack it."
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