Why UTIs are sometimes reoccurring

While the majority of bacteria that cause urinary tract infections can be wiped out with antibiotics, some manage to avoid elimination by remaining dormant, and new research from Duke University has found the possible reason why this happens.

These hard-to-kill bacteria (also known as “persisters”) are essentially put to sleep by a protein called HipA. A better understanding of this protein could lead to new ways to combat drug-tolerant infections, Dr. Richard G. Brennan, professor and chair of biochemistry at the Duke University School of Medicine, and his colleagues reported Wednesday in the journal Nature.

Dr. Brennan’s team found that particularly potent mutant versions of HipA can cause multidrug tolerance in urinary tract infections (UTIs). They explain how these mutations allow the protein to have an enhanced effect, allowing it to help a greater number of bacteria become dormant. In addition, this discovery opens up a new way to combat drug resistance.

Mutations increase persisters, raising risk of reinfection

Dr. Brennan explained to redOrbit via email that researchers have known of the existence of a potent mutant version of HipA, called HipA7, since the 1980s. This mutation, he said, can cause a dramatic increase in the number of “nondividing, metabolically quiescent” persister cells.

“The HipA7 mutant contains two changes in its protein sequence compared to the wild type HipA protein – a substitution of residue Gly22 by a serine and a substitution of residue Asp291 by an alanine,” he said. He and his collaborators found not only the previous version of HipA7, but also “a new high-persister form that encoded a HipA protein in which residue 86, normally a proline, was changed to a leucine. This is abbreviated hipA(P86L).”

Both types of the mutation “form 1,000-fold more persisters” than the regular version of HipA, and both also showed the ability to withstand doses of different antibiotics. These drugs typically work by targeting the active processes in a cell and corrupting their products. However, since persisters are now growing and are far less active metabolically, the normal targets of many of these drugs are not used by the cells, making antibiotics far less effective against them.

Having observed all of this in the laboratory, Dr. Brennan said that the team then looked to see if they could find similar processes occurring in nature. They focused on strains of E. coli known to cause UTIs. Not only were both versions of the HipA mutation “present in many of the disease causing strains,” but that they “resulted in multidrug tolerant bacteria,” resulting in an increased number of persisters that survived treatment and could cause reinfection.

Searching for inhibitors to reduce HipA-induced persisters

For now, the study authors said that they have to learn more about the biochemical function of HipA, which is a serine-protein kinase, meaning it adds a phosphate group to its substrates. The mechanism through which it does this is unknown, however, so one goal is to see if they can find inhibitors of this kinase. They also said that they are looking for other high persistence protein mutations that work by the same type of mechanism utilized by HipA7 and HipA(P86L).

“In the longer-term,” Dr. Brennan told redOrbit, “if inhibitors could be found that had the ability to decrease or totally eliminate the HipA-induced persisters, then we would try to develop one or more of these inhibitors into a therapeutic, which could be given with the normal antibiotic regimen to treat UTIs.”

“This way we would expect that the antibiotic would be effective in killing the normal planktonic bacteria and that we would also hinder their ability to become persisters,” he added. “Hence, after full treatment one could hope that all the growing bacteria are dead and no persisters are left behind to allow reinfection. This is long-term goal but requires a great deal more basic research before it might be realized.”

(Image credit: US Dept. of Agriculture, Agricultural Research Service)