For Scott Hultgren, urinary tract infections are the canary in the coal mine for antibiotic resistance.
“Since the mid 2000s, the difficulty of treating UTIs has been steadily rising,” Hultgreen, director of the Center for Women’s Infectious Disease Research at Washington University School of Medicine in St. Louis, told The Daily Beast. There are around 8 million UTIs diagnosed each year in the United States, making up around 25 percent of all infections.
Most of the time, a course of antibiotics can knock out your average UTI. But for about 25 percent of women, the infection comes back, and develops into recurrent UTIs. “A lot of these patients end up getting put on suppressive antibiotic therapy that they take every day, sometimes for months,” Hultgren said. “It’s not an adequate treatment option.”
ADVERTISEMENT
But there might be an alternative therapy. Hultgren is working to develop a precision antimicrobial for UTI. Unlike traditional, antibiotics, which wipe out good and bad bacteria indiscriminately, precision treatments would target the specific bug responsible for the urinary tract infection, while leaving the rest intact.
Researchers are working to develop these specific, targeted compounds for other infections, like Clostridium difficile, as well. Honing in on only the problem bacteria for a particular infection would help slow the march of antibiotic resistance—and targeting the harmful bacteria directly also allows the normal, healthy microbiome to remain intact during treatment.
“In the last 10 years, we’ve realized that the majority of microbes in association with our body are beneficial, and they play a role in our health,” César de la Fuente, a postdoctoral fellow in the Synthetic Biology Group at the Massachusetts Institute of Technology, said. “We don’t really want to affect those microbes; we want to target the ones causing harm.”
Scientists are using a variety of different strategies to develop targeted treatments for UTI, and other conditions like pneumonia and skin infections. They’re deploying the gene editing system CRISPR to cut up bacterial genetic codes, and re-engineering proteins that are naturally produced by the immune system to fight bacteria, called antimicrobial peptides, to target a specific bug.
Hultgren’s strategy involves building a comprehensive understanding of this individual bacteria, and blocking an activity crucial to its function. Urinary tract infections occur when E. coli bacteria, found in the gastrointestinal tract, creep up into the urethra, where they multiply and cause uncomfortable burning and the constant need to pee.
Hultgren and his team honed in on a tiny molecule on the tip of E. coli’s hair-like appendages, or their pili. The molecule, called FimH, helps the bacteria stick to the inside of the bladder.
That FimH is what Hultgren hopes to target using a class of compounds that prevent FimH from binding in the first place, called mannosides.
“It would unstick all of the bacteria,” Hultgren explained. He and his colleagues have made progress toward a working therapy, publishing an article in the journal Nature in June 2017 that shows that the compound works in mice, flushing out infections when they’re present and—better yet—preventing the E. Coli related to UTI from taking up residence in the intestines in the first place.
For Hultgren, the ubiquity of urinary tract infections makes them an ideal target for precision antimicrobials. “Right now, we have a lot of antibiotics going into the guts of mostly women, and there’s no sign it’s getting better,” he said.
Hultgren started a small biotechnology company called Fimbrion, which partnered with the pharmaceutical company GlaxoSmithKline to develop the method into a therapy for humans. “The project is ongoing but there are no timelines yet that we can share externally,” wrote Michael Bishop, director in the Discovery Partnerships with Academia program at GSK, in an email to The Daily Beast. “The next step would be clinical trials, but we are not at that stage yet.”
Clostridium difficile, or C. diff, an infection typically picked up in hospitals that infects the colon, is another key bacteria scientists are looking to target with precision antimicrobials. Drug resistance to C. diff is a major threat, according to the CDC. “This idea of precision medicine is a trendy topic,” Robert Fagan, a senior lecturer in molecular biology and biotechnology at the University of Sheffield, said. “But in the case of C. diff, it’s really, really critical.”
For C. diff, keeping healthy bacteria intact by using a targeted treatment is particularly key—because a disrupted gut microbiome is what lets the infection take root in the first place. “With C. diff, normal, healthy bacteria are in some way badly disturbed to make someone susceptible to infection, usually because they’re given an antibiotic for something else,” Fagan said. “The problem is that at this moment, our best options for treating them is to give them more antibiotics.”
About 20 percent of C. diff infection cases recur after the first round of antibiotics, and one recurrence makes it more likely that patients will have another. Treating the initial infection with something that keeps the gut microbiome intact could likely prevent that cycle from starting, he said.
Fagan conducted research with the company Pylum Biosciences on a compound that, in mice, selectively kills C. diff by latching on to the proteins on the bacterial surface and punching a hole through the membrane. Pylum hopes to file a pre-Investigational New Drug application with the Food and Drug Administration in the fall, which would allow them to conduct safety studies on their compound in humans, said David Martin, chief executive officer at Pylum Biosciences. He said that they’re planning to start a clinical trial in 2019.
While precision antimicrobial treatments are, in theory a great approach to tackling antibiotic resistance, and limiting the disruption in the microbiome, there’s a long road to picking them up from the pharmacy—including to make sure they work as well in humans as they do for animal models in the laboratory. Antibiotics also still work, Martin said, and they’re both cheap and accessible.
“The argument has to be, you better make changes now, or soon enough they won’t be working and you won’t have anything left,” Martin said. And while it’s less of a problem for UTIs and C. diff, which have their own specific bacteria, precision antimicrobials require that doctors know exactly what bug they’re dealing with. “You need a diagnostic,” he said.
However, de la Fuente said, there’s a consensus in the research community, at least, that this is the best way forward. “There’s such a need to come up with alternatives, and to be trying different things,” he said. “I think there’s a push and an excitement, driven by the urgency of the need.”
