Urinary Tract Infection

Structures Reveal Basis of Recurring Urinary Tract Infections

While the best antibiotics can wipe out most of the bacteria that cause notoriously difficult urinary tract infections, a few “sleeper cells” often remain. These “persisters,” as they are called, survive by going dormant, essentially sleeping through the attack that kills off their more active brethren.

A new study done at Duke University has shown that a protein called HipA acts as a kind of molecular Sandman, putting bacterial cells to sleep so they can live another day. The researchers behind the finding say understanding HipA may give them a way to combat drug-tolerant infections.

Their research, published July 29th 2015 in Nature, found that particularly potent, mutant versions of HipA cause multidrug tolerance in urinary tract infections. It explains how these mutations boost the protein’s slumberous powers to help more bacterial cells avoid being obliterated by antibiotics.

A release from the university quotes Richard G. Brennan, Ph.D., professor and chair of biochemistry at Duke University School of Medicine, as saying, “This discovery presents us with a new method for combating multidrug tolerance. If we can find a way to block this protein, we may be able to awaken these problematic cells or keep them from falling asleep in the first place, so that we can eliminate them for good.”

Multidrug tolerance occurs when a disease-causing microorganism manages to survive or tolerate an onslaught of antibiotics or other antimicrobials. It is not to be confused with the related phenomenon multidrug resistance, where pathogens alter their genetic makeup to become resistant to specific drugs. In multidrug tolerance, microbes instead change their behavior, temporarily shutting down cellular functions that are the typical targets of drugs so they are not seen as a threat.

Because only about one in a million bacterial cells employs this tactic, it is particularly difficult to decipher how these so-called “persisters” are able to emerge. More than three decades ago, researchers studying the common bacteria E. coli found that a protein called HipA was responsible for driving cells into dormancy. Studies showed that a mutated version of HipA, called HipA7, could generate 1000 times as many persisters.

Despite these advances, it still wasn’t clear whether the HipA protein played a role in human disease. To investigate this possibility, the Duke researchers and their collaborators at Northeastern University sequenced the hipA gene of multiple E. coli samples from patients with urinary tract infections. They found that nearly two dozen of the samples harbored the hipA7 “high persister” mutations, which they then showed were responsible for causing recurrent infections in patients.