Finding nonantibiotic solutions to resistant UTI - Drug Discovery News

Urinary tract infections (UTI) are one of the main reasons women visit doctors, and they are one of the main hotbeds of antibiotic resistance. Yet, little is known about what causes these infections, especially recurrent ones, and how to effectively treat them without antibiotics. A handful of researchers are breaking the trend and pushing for sustainable solutions.  

Although UTI occur in both male and female patients, they are far more common in women and girls (1). Around eight percent of women in the United States report having a UTI every year, and more than half of women will get at least one in their lifetime (2). Even after treatment with antibiotics, nearly a third of those patients experience another UTI within the next few months (2). Escherichia coli  are the most common cause of UTI and the most well studied, but other pathogens such as Klebsiella pneumoniae  are also responsible. 

UTI is the canary in the coal mine because there are more antibiotics to treat UTI than any other infectious disease in the United States. 
- Scott Hultgren, Washington University in St. Louis

Although about a quarter of UTI can be cleared by simply drinking plenty of fluids and taking ibuprofen, these infections account for around eight percent of antibiotic prescriptions in the US, second only to respiratory infections and sore throats (3,4). Often, these prescriptions are for longer durations than necessary and for antibiotics that are not recommended by the Infectious Diseases Society of America guidelines (5). Doctors often prescribe second-line antibiotics in cases when first-line antibiotics would be recommended. Researchers have not yet pinpointed what's behind this misprescribing, but they are working on antibiotic stewardship interventions to diminish them.

"Urinary tract infection is the canary in the coal mine because there are more antibiotics to treat UTI than any other infectious disease in the United States," said Scott Hultgren, a microbiologist at Washington University in St. Louis. 

For patients with recurrent UTI, antibiotic resistance is a predominant concern among healthcare providers and scientists. Hultgren said, "We're reaching an antibiotic tipping point where the antibiotics just aren't going to work anymore, and we're seeing that more and more in the clinic."

Alongside drug resistance, antibiotic treatment for UTI wipes out both good and bad bacteria, reducing the diversity of species in the gut microbiome at least temporarily (6). Antibiotics lower the relative abundance of key members of the microbiome community that keep the gut healthy (7). Although there is mixed evidence on how long it takes for the microbiome to recover, the lasting effect on its diversity is one suspected culprit of recurrent UTI (8). 

"We now believe these antibiotics are making the problem worse," said Ashlee Earl, a microbiologist at the Broad Institute of MIT and Harvard.

With the rising concern of antibiotic resistance and the extreme effects of antibiotics on the microbiome, researchers are searching for nonantibiotic treatments for UTI. Some target E. coli as it binds to the bladder wall, while others look further upstream at the gut microbiome and molecular differences in the bladders of people with recurrent UTI.

Starting in the bladder

During a UTI, E. coli latches onto mannose molecules on cells in the urogenital tract using the protein FimH. The bacteria then replicate and create a biofilm, causing an infection.

Clinicians who commonly treat UTI often recommend that people take D-mannose, which is a type of sugar produced by the body and found in certain fruits and vegetables. It binds to E. coli's FimH adhesin, decreasing E. coli's ability to bind to the bladder wall (9). Although there is mixed evidence on the effectiveness of D-mannose, many doctors still recommend it because there are no known negative side effects (10). 

Researchers are interested in understanding and targeting the upstream causes of urinary tract infections, especially recurrent ones.

Credit: iStock.com/VectorMine

Inspired by D-mannose's activity, Hultgren and his team decided to take D-mannose one step further. They developed a vaccine to target the same adhesin on E. coli, FimH (11). "It made sense to target FimH for a vaccine because it seems to be involved in every step of the pathogenesis cascade. Plus, it's extracellular, which makes the target accessible," Hultgren said.

More than two decades ago, Hultgren and his team tested a version of the vaccine in mice and monkeys with promising results (11,12). The vaccine has since gone through Phase 1 clinical trials in humans (13). In these trials, clinicians administered the shot on four occasions: days 1, 31, 90, and 180 of the trial. It successfully induced anti-FimH antibodies that reduced adhesion of E. coli  to bladder cells (14). 

According to Hultgren, these trials resulted in a 70-80 percent reduction in recurrent UTI after vaccination, although the data has yet to be peer reviewed and published. Because of the success in early trials, the FDA approved the vaccine for compassionate use in 2017, which has allowed treatment for a handful of patients with severe UTI recurrence (15). 

Building off of the promising D-mannose results, Hultgren and others are developing mannosides as another way to treat UTI. These compounds work similarly to D-mannose and mimic the FimH adhesion to block bacteria from binding the bladder cells (16). The team designed mannosides to have a stronger bond with FimH by altering the chemistry of specific regions of the D-mannose molecule, including the tyrosine gate and hydrophobic pocket. As a result, mannosides inhibit FimH function with a 1 million-fold higher potency than D-mannose (17).

Mannosides and the FimH vaccine could work well together, said Hultgren. "The nice thing about the mannoside is it can work instantaneously, whereas with the vaccine, you have to wait to build up the immunity."

Mannosides and the FimH vaccine are just two of many nonantibiotic therapies in development. Others include pilicides, which disrupt E. coli's  ability to create adhesive structures in the first place, and phage therapy, which aims to infect and lyse drug-resistant bacteria (2,18). 

Digging deeper

Although FimH vaccine and mannosides will likely reduce the number of UTI that patients experience, other researchers are interested in understanding and targeting the upstream causes of these infections. Despite the prevalence and persistence of UTI, the mechanism by which they occur is still not well understood. Although researchers previously thought that higher levels of E. coli in the bladders of some people led to recurrent UTI, the story proved a bit more complicated. 

"We've been interested with our collaborators for a long time [in] the underpinnings of recurrent UTIs," said Earl, which typically constitute two infections within a six-month period. Because bacteria that cause UTI often populate the gut microbiome, Earl and her colleagues, including Hultgren, wanted to determine if and how the gut microbiome influences recurrent UTI.

"What it is about the microbiota that makes it either colonization-resistant or colonization-sensitive? If we could get that zeroed in on what is that composition of bugs, we might be able to fix it," said Hultgren.

Earl, Hultgren, and their teams conducted a multiomic longitudinal study on the underlying mechanisms of recurrent UTI (6). They found that patients with recurrent UTI and healthy controls experienced similar levels of gut-to-bladder transmission of bacteria. Plus, the E. coli  strains were genetically similar between both groups. 

People with recurrent UTI, however, had lower levels of bacteria that support immunomodulation and anti-inflammatory effects in the gut such as those in the Faecalibacterium  and the Akkermansia  genera. In line with previous work in mice, the researchers found that antibiotics failed to fully eradicate UTI-causing bacterial strains from the gut (19).

If this imprint is occurring in humans, which I think it is…it could begin to explain why history is the major risk factor for recurrent UTI. 
- Scott Hultgren, Washington University in St. Louis

Earl has since been following up on these results to identify possible differences in the transcriptional state of E. coli in the gut microbiome, which might explain why some people are more susceptible than others. She also hopes to investigate distinctions between people with acute UTI and people with recurrent UTI.

"The work we did answered some questions, but it also left open a bunch of questions as well," said Earl.

In a mouse model of recurrent UTI, Hultgren and his team showed that an overexuberant inflammatory response to an initial uropathogenic E. coli  infection can leave a molecular imprint on the bladder, meaning that the infection significantly alters mouse bladder cells (20). Cells from the urinary tracts of mice with recurrent UTI were smaller than cells from healthy mice and had defective differentiation. Hultgren believes that this imprint then increases susceptibility to subsequent UTI and hopes to study this idea further. 

"If this imprint is occurring in humans, which I think it is…it could begin to explain why history is the major risk factor for recurrent UTI," said Hultgren.

Another outlying question for UTI researchers is whether the urinary microbiome, the gut microbiome, the vaginal microbiome, or some combination of them is most influential. Hultgren is currently investigating this question.

Understanding more about the underlying drivers of recurrent UTI, especially changes in the microbiome, could lead to even more treatment and prevention options for people suffering from repeat infections. Even therapies like fecal transplants to improve the diversity of the microbiome may be promising given Earl and Hultgren's findings.

"We're attacking this problem from different angles," said Hultgren. "There's no shortage of UTI to treat."

References

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