Novel agent may protect against major UTI pathogen

In the search for new ways to combat urinary tract infections, researchers have shown that an experimental drug that stabilizes a protein called HIF-1alpha protects human bladder cells and mice against a major UTI pathogen.

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The drug may eventually provide a therapeutic alternative or complement to standard antibiotic treatment, say study authors from the University of California, San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.

The study was published online in by PLOS Pathogens (April 30, 2015).

HIF-1alpha is known to influence the innate immune response, researchers say. Like many regulator proteins, HIF-1alpha is relatively short-lived. To increase HIF-1alpha levels, researchers have developed drugs that delay its breakdown. This same pathway has been the target for drugs now in advanced clinical trials for treatment of anemia.

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In the current study, lead author Victor Nizet, MD, and colleagues explored the use of HIF-1alpha-stabilizing drugs to boost the innate immune response to uropathogenic Escherichia coli (UPEC) bacteria, a major cause of UTIs. In healthy human urinary tract cells, treatment with the drugs increased HIF-1alpha levels. Such cells were then more resistant to UPEC attachment, invasion, and killing than human urinary tract cells with normal HIF-1alpha levels, Dr. Nizet’s team said in a University of California, San Diego news release.

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Using a mouse model of UTI, the researchers showed that administration of HIF-1alpha stabilizers directly into the bladder protected against UPEC infection. They also found that invasion of bladder cells, a critical early step in the infection process, was reduced in treated mice compared to untreated mice.

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To verify the importance of HIF-1alpha in the defense against UPEC infection, the researchers studied mice with reduced HIF-1alpha levels. Exposed to UPEC, these mice were more susceptible to bladder infection, and pre-treatment with HIF-1alpha stabilizers made no difference. This demonstrates that the drugs combat UTIs through their effect on HIF-1alpha.

Finally, the researchers examined whether treatment with HIF-1alpha stabilizers would be beneficial against an established UTI. To do this, they infected mice with UPEC first and then administered the drugs into the bladder 6 hours later. The treated mice had a more than tenfold reduction in bladder colonization with the bacteria, demonstrating that HIF-1alpha stabilization is beneficial even after the initial infection.

“The ultimate goal of this research will be to advance HIF-1alpha stabilizers toward clinical trials in humans, using versions of the drug that can be taken orally and reach the urinary tract,” Dr. Nizet said.

One study co-author is an employee of Aerpio Therapeutics.

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