Researchers at UCSD School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences published a report studying the role of a new experimental drug in helping to protect against urinary tract infections on April 30.
The purpose of the study was to determine whether drugs that work to stabilize the protein transcriptional regulator hypoxia-inducible factor-1, or HIF-1alpha, can increase the innate immune response that blocks the entrance of uropathogenic E.coli, or UPEC, bacteria into the body.
According to corresponding author and professor of pediatrics and pharmacy at Skaggs Dr. Victor Nizet, researchers first realized the significance of HIF-1alpha and its role in innate immunity through the examination of previous studies of mice that had genetic deletion of HIF-1alpha in their white blood cells or in their skin cells.
Other studies further demonstrated that these mice were also more susceptible to bacterial infection, and their cells had difficulty killing pathogens like UPEC.
While HIF-1alpha typically is a short-lived regulator protein, there have been experimental drugs designed to slow the breakdown process and prolong the protein’s stabilizing effect. It was these drugs that Nizet and his colleagues hoped to demonstrate could be utilized in boosting HIF-1alpha levels to combat pathogens that lead to UTIs.
Nizet also told the UCSD Guardian that past research further aided this new avenue of study.
“In earlier work, we published that these drugs, when administered topically, could treat skin infections with drug-resistant staph bacteria,” Nizet said. “In the current paper, we are extending our work to a super problematic type of infection — UTIs, which have a high rate of recurrence and since antibiotic resistance is increasing in the most common pathogens causing UTI[s], especially E. coli.”
Following the confirmation of the significance of HIF-1alpha levels, Nizet and his colleagues began conducting their research using human epithelial cells, or bladder cells, and a mouse model of a UTI.
First, in order to confirm the importance of HIF-1alpha in preventing UPEC infections, researchers examined mice with reduced levels of the protein. In doing so, they discovered that, when exposed to UPEC, these mice were more likely to experience a UTI infection, showing that HIF-1alpha controlled the expression of genes in the bladder important for natural immunity.
Researchers then analyzed whether or not the experimental drugs would be beneficial in treating established UTIs by infecting the mice with UPEC and administering the drugs six hours later.
Results from these experiments demonstrated a significant decrease in bacteria presence within the bladder cells following treatment that limited the amount of damage done to the bladder and kidneys of the host.
The results of the study and previous use of the drugs in other therapies, such as in treating anemia, could prove valuable in helping to develop necessary new methods for treating infections.
“If HIF-boosting drugs are as safe as they seem in anemia therapy and gain Food and Drug Administration approval, it might create an easier pathway to explore their use in infectious-disease scenarios alongside standard antibiotics,” Nizet said.
Nizet and his team are further studying oral formulation of these types of drugs and exploring their benefits in a wide variety of different types of infections through laboratory models.