Howard Shuman directs the Howard T. Ricketts Laboratory—a BSL-3 biocontainment lab operated by the University of Chicago in Lemont, Illinois named after the early 20th century physician researcher who discovered that ticks and lice were the vectors for Rocky Mountain spotted fever and typhus, respectively.
The two Howards have a few things in common. Both professors at the University of Chicago pursued the study of microbes that replicate inside host cells. Ricketts, however, succumbed to typhus while studying a Mexico City outbreak in 1910 at his prime, age 39, because antibiotics had not yet been discovered.
Today, Shuman’s laboratory studies intracellular bacteria at a time when antibiotics have become less effective at fighting infections around the world due to resistance. Using these bacteria (some also named after Ricketts), Shuman and his colleagues have demonstrated a new method for finding antimicrobial properties in already-approved drugs.
“I’m a much-less-good cell biologist than the bacteria I work on,” jokes Shuman, who notes that many of these bacteria tailor-make their own vacuolar compartments within the cell for growing. This new study came out of a ‘failed’ study a few years prior.
His research group wanted to screen for small molecule inhibitors that could disable the virulence factor(s) of Legionella pneumophila, the bacterial culprit behind Legionnaires’ disease. The team was initially discouraged to find that each ‘hit’ compound was targeting the host cell macrophages that contained the L. pneumophila and not its virulence factor(s).
“Let’s see if we can figure out something useful from here,” Shuman recalls thinking. Some of the compounds blocked the process of phagocytosis in the macrophages, preventing the bacteria from being taken up. “In the back of my mind, I wondered, are there other host functions that the bacteria need to survive?”
And what if you could find drugs directed against host cell functions that prevented the bacteria from growing? Better yet, what if they were drugs that have already been safety-tested, studied intensively, and approved by the U.S. Food and Drug Administration (FDA)?
“Why not short circuit those difficulties and stumbling blocks of drug development by [screening] already approved drugs?” says Shuman.
A team of collaborators at University of Chicago did just that, reporting this week in mBio® that they screened a panel of 640 FDA-approved drugs against four intracellular bacterial pathogens: Coxiella burnetii (which causes Q fever), Legionella pneumophila (Legionnaires’ disease), Brucella abortus (brucellosis), and Rickettsia conorii (Mediterranean spotted fever).
By using fluorescently labeled bugs grown in human THP-1 macrophage-like cells, the researchers measured which drugs inhibited bacterial growth by 80% or more. They ruled out drugs that were purely toxic to the host cells and any drugs that were known antibiotics or antivirals. The result was a list of 101 known drugs that exhibit antimicrobial properties, presumably by blocking critical cellular functions in the host cells.
Topping the list were nine drugs that inhibited growth of three of the four bacteria. Those included some household names like loperamide, an antidiarrheal otherwise known as Imodium®, and clemastine, an allergy medicine sold under the name Tavist®. Shuman is quick to point out that this study is merely a proof-of-principle, showing that these drugs work to stall infection in the laboratory dish only.
Shuman thinks some of the drugs may not work through their primary targets, but rather through secondary effects that alter cellular signaling or metabolism. The drugs generally fell into three classes—those that target G-protein coupled receptors, those that interfere with calcium transport (both important for proper cell signaling), and those that affect cholesterol synthesis (perhaps a key ingredient for vacuole membranes).
And, Shuman notes, these drugs with known safety and side effect profiles make good starting points for discovering new types of antimicrobial drugs that could act in conjunction with traditional antibiotics. They might also be important for finding cures for the roughly 5% of C. burnetii and B. abortus infections that become chronic and ultimately fatal.
“There are always emerging infections of all sorts—bacteria, viruses, parasites. Working up a new therapy for such things take time,” says Shuman. “If you knew how to limit an infection by interfering with the host cell, you might be able to intervene even without completely understanding the new pathogen.”