It’s hard to find an innovation in modern medicine that has impacted human life as much as antibiotics — compounds such as penicillin, which kill or inhibit the growth of bacteria. Diseases that once claimed millions of lives are today treated with few complications (for the most part). However, the overuse and misuse of antibiotics have contributed to a very real public health crisis — the evolution of antibiotic-resistant strains of disease-causing bacteria. These “superbugs,” causing diseases such as extensive drug-resistant tuberculosis (XDR TB), are so dangerous because they cannot be targeted by common antibiotics, making them much more difficult to treat and potentially life-threatening. The development of new or alternative antibiotic therapies is therefore more important than ever.
To this end, University of Chicago researchers have developed a novel method to identify non-antibiotic drugs that could one day help curb bacterial infections — by studying drugs already approved by the FDA for other purposes. In a study published July 29 in mBio®, the online open-access journal of the American Society for Microbiology, the team, led by senior author Howard Shuman, PhD, professor of microbiology, looked at a panel of 640 FDA-approved drugs that have known safety and side effect profiles.
Testing each of these for its ability to disrupt the growth of bacteria within human host cells, the team discovered 101 drugs that show promise in fighting bacterial infections. The researchers showed this in four bacterial strains: Coxiella burnetii (which causes Q fever), Legionella pneumophila (Legionnaires’ disease), Brucella abortus (brucellosis) and Rickettsia conorii (Mediterranean spotted fever). Among the compounds they isolated were 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.
“With the increasing prevalence of antibiotic resistance among clinically-relevant bacterial pathogens, the requirement for alternative treatment options is at its highest,” said study author Daniel Czyz, PhD, a post-doctoral scholar in Shuman’s lab during this study (now in the lab of Sean Crosson). “We used an approach where we target human cells, not the bacteria, to interfere with host processes that get hijacked by bacteria during infection, but also to make them more resistant and able to clear off infection on their own. This approach can circumvent the problem of antibiotic resistance and when coupled with existing therapies, can shorten the treatment and eliminate any complications associated with a specific infection.”
However, Czyz cautions that these results do not mean that these drugs can immediately be used as a therapy in humans.
“Although we have identified potential novel agents against intracellular bacterial pathogens, our study only reflects their effectiveness in a dish, on a cellular level,” said Czyz. “We still do not understand their effect on the organismal level. Therefore, additional animal work needs to get done before any of these results can be translated to humans.”
Shuman’s lab group did the experiments on C. brunetii and L. pneumophila, while Sean Crosson’s group at University of Chicago carried out the B. abortus work, and Juan Martinez’s group, now at Louisiana State University in Baton Rouge, performed the R. conorii studies. The work, which was done at the Howard T. Ricketts Laboratory, a biocontainment laboratory operated by the University of Chicago in Lemont, Illinois at the Argonne National Laboratory campus, shows that known drugs that interfere with host cell properties can stall intracellular bacterial infections.
“There are emerging infections of all sorts—bacteria, viruses, parasites. Working up a new therapy for such things take time,” said 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.”
The study was funded by the US National Institutes of Health. This story was adapted from a release by the American Society for Microbiology.