As antibiotic resistance grows, researchers turn to copper for UTI treatment

Researchers at the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) are investigating how the body uses the essential trace mineral to fight urinary tract infections (UTIs), how bacteria manage to survive that attack and whether those discoveries could eventually lead to new ways of treating infections that are increasingly difficult to control with antibiotics.

The research, supported by a $1.48 million grant from the National Institutes of Health (NIH), builds on previous findings from the lab of Dr. Sarguru Subash, an associate professor in the VMBS Department of Veterinary Pathobiology, showing that the body pumps copper into the urinary tract during infection to kill the UTI-causing bacteria.

“We know that copper plays an important role, but that also raises so many questions about how these pathogens adapt to the presence of increased copper,” Subash said. “If we better understand how the bacteria overcome the host-imposed copper resistance, then we can develop therapies that make the bacteria more susceptible to copper and, more broadly to everything that the immune system throws at them.”

Turning a nutrient into a weapon

Copper is an essential nutrient for both people and animals, but in the right environment and concentration, it can also be toxic to bacteria.

The immune system takes advantage of that property when responding to infection.

As part of the body’s early, or innate, immune response, specialized immune cells can engulf invading bacteria and expose them to an antimicrobial mixture that includes copper. During a UTI, Subash’s previous research has shown that the body increases copper levels in the urine.

But bacteria are not defenseless. Because they encounter copper naturally in the environment, many bacteria have evolved mechanisms that allow them to remove or detoxify the metal.

“Bacteria do have adaptations, but when it’s presented in the context of this cocktail, the bacterial defense mechanisms are not as effective,” Subash said. “Sometimes the balance tips in favor of the host, so we can control the infections. Other times, the balance tips in favor of pathogens. As a result, we get clinical disease.”

That creates what Subash describes as a tug-of-war between the host and pathogen: sometimes, the immune system successfully controls bacterial growth before it causes noticeable illness; other times, bacteria overcome those defenses, allowing an infection to become established.

Understanding what tips that balance could reveal new vulnerabilities that researchers can target to control bacterial infections.

Learning how bacteria fight back

His new project will examine the interaction from both sides — how the body deploys copper and how bacteria respond once they encounter it.

Part of the research will investigate the genetic mechanisms that allow UTI-causing bacteria to tolerate increased copper and continue growing despite the immune system’s attempts to stop them.

Another part will explore early evidence found by the team that copper may do more than inhibit bacterial growth. It could interfere with hair-like structures on the surface of bacteria called fimbriae, which allow the bacteria to attach tightly to cells lining the bladder.

That attachment is critical because one of the urinary tract’s physical defenses is urination itself, according to Subash. Bacteria that cannot firmly attach to the bladder lining are more likely to be flushed from the body.

The researchers will also study ceruloplasmin, a copper-containing protein that Subash’s previous findings suggest may help deliver copper during a UTI.

Finally, because metals such as copper can damage the body’s own cells at high concentrations, the body carefully controls how they are transported and stored. Subash’s team will investigate how ceruloplasmin helps mobilize copper during infection and what role that process plays in the immune system’s ability to control invading bacteria.

Together, those studies will help researchers better understand the host-pathogen interface — where the body’s defenses and a disease-causing organism interact.

Helping the immune system finish the job

The project’s ultimate goal goes beyond understanding how the process works. Subash’s team is also investigating whether it can use that knowledge to develop new treatments.

The researchers previously identified an experimental antimicrobial compound that becomes more effective when copper is present. They will now modify and test related compounds to identify potential candidates for future therapies that could work alongside the immune system’s existing defenses.

This host-directed approach could be particularly valuable as bacteria become increasingly resistant to antibiotics.

“We are very interested in understanding the basic aspects of how the immune system controls pathogens so we can develop next-generation antimicrobials that not only are focused on directly killing bacteria but also work synergistically with the immune system,” Subash said.

Subash cautioned that any clinically available copper-dependent treatment is still likely years away, but the current research could provide an important early step toward developing new options for difficult-to-treat UTIs.

Potential beyond UTIs

While the research is focused on UTIs, its potential impact could extend beyond the bladder. Some of the same bacteria that cause UTIs can also cause infections in other parts of the body, meaning discoveries about how they respond to copper could eventually inform treatments for other bacterial infections.

The work could also have implications for veterinary medicine, where UTIs are a recurring problem in animals such as dogs. Before those possibilities can be explored, Subash and his team are focused on understanding the fundamental relationship between the body’s copper defenses and the bacteria trying to overcome them.

“The main innovative aspect of this project is looking comprehensively at how the pathogen responds and how the host uses copper and then tying together both of these basic science discoveries with a translational goal,” Subash said. “It’s a full circle.”