Distinguished Professor Kim Lewis from Northeastern University, along with his colleagues has remarkably discovered a common mutation in E. coli from urine samples of about 500 people suffering from recurrent urinary tract infections (UTI). The breakthrough could help patients with UTI with a new and more effective therapeutic regime which seems to be more effective.

The ‘Persister’ Theory

According to the American Urological Association, approximately 150 million cases of UTI are reported globally each year, amounting to $6 billion in healthcare services. The majority of these cases are caused by the bacterium E. coli. Standard treatment involves antibiotics; however, the infection usually relapses once the patient stops taking medication.

Lewis, Director of the Antimicrobial Discovery Center has dedicated many years to studying the reason of recurring UTIs. A paper published in 2001 revealed the answer: a subpopulation of E. coli – ‘persisters’ – that had developed antibiotic ‘tolerance’. The latter (unlike ‘resistance’, which requires a specific genetic mutation) occurs when the bacteria lay dormant, waiting for the medication’s effect to wear off. Then they come out and start multiplying.

What Exactly Is A Persister Cell?

Bacteria are single-cell organisms – they multiply exponentially until an army of cells infect the host. However, at times the cell division produces only one active cell and one dormant cell. The active bacterial cell continues to grow and reproduce, whereas the dormant cell – the ‘persister’ – stops growing and becomes dormant in a ‘sporelike state’.

Since antibiotics attack only actively reproducing and functioning cells, these dormant bacterial cells escape the ambush. Once the attack subsides, they become active and start to re-spread the infection, saving their population.

The Study: Finding A Common Aspect

Lewis and his team took a large sample of E. coli isolates from patients with recurring UTIs. Pooja Balani, then a doctoral student in Lewis’ lab among the first authors of the paper performed genetic screening of both test-tube cultures of E. coli and the samples from patients to find a mutation. After countless hours of investigation, it was discovered that many of the isolates had a similar mutation in the ‘hipA’ gene, which had previously been seen in test-tube experiments.

The hipA gene codes for a protein that acts as a toxin. The latter is generally held in check by another protein – antitoxin – that is coded for by the gene ‘hipB’. Lewis explained that such toxin-antitoxin pairs are spread around the entire chromosome of all bacteria. However, a mutation in either gene can disrupt the balance – overproduction of toxin could shut down the cell and transform it into a ‘persister’. “The hipA mutation gives rise to about 1,000 times more persisters than a gene without it”.

Important Implications: Why Urinary Tract Infection Recurs

An understanding of this genetic mechanism could help clinicians offer customized treatment strategies to patients with relapsing UTIs. “We can track whether the patient has E. coli with a hipA mutation, and if so, introduce a pulse-dosing regimen,” stated Lewis in the study published in the journal Nature.

According to Lewis, pulse-doing is a straightforward method: the patient is given an antibiotic that kills all actively reproducing cells. Before the persister cells start to become active and multiply, the antibiotic is administered again. When this procedure was repeated a couple of times in test-tubes, Lewis and team successfully eradicated the entire bacterial population. He believes the same is possible in humans.