Scientists Identify The Cause Of Antibiotic Resistance

For the first time, scientists from Newcastle University have confirmed that bacteria can change form to avoid being detected by antibiotics in the human body.  After studying samples from elderly patients with recurring urinary tract infections with state-of-the art techniques, the team identified that bacteria can lose its cell wall which the most common target of many groups of antibiotics.

The research conducted by the Errington lab completely changes the way we think about the bacteria’s ability to survive without a cell wall. The report on this “L-form switching” was just published in Nature Communications.

The World Health Organisation has declared antibiotic resistance as one of the biggest threats to global health, food security, and development nowadays.

Lead author, Dr. Katarzyna Mickiewicz researcher at Newcastle University said: “Imagine that the wall is like the bacteria wearing a high-vis jacket. This gives them a regular shape (for example a rod or a sphere), making them strong and protecting them but also makes them highly visible—particularly to human immune system and antibiotics like penicillin”.

He added, “What we have seen is that in the presence of antibiotics, the bacteria are able to change from a highly regular walled form to a completely random, cell wall-deficient L-form state- in effect, shedding the yellow jacket and hiding it inside themselves. In this form the body can’t easily recognise the bacteria so doesn’t attack them—and neither do antibiotics.”

The research which studied samples obtained through a collaboration with clinicians at the Newcastle Freeman Hospital part of Newcastle upon Tyne Hospitals Foundation Trust organized by Dr. Phillip Aldridge and Dr. Judith Hall found that when antibiotics are present in a patient, say with a UTI, receiving penicillin or other cell wall-targeting antibiotic, then the bacteria have the ability to change form by losing the cell wall which is frequently the target of the antibiotic.

This video captures the transition on osmoprotective media from L-form to walled form after the antibiotic was removed. Credit: Newcastle University, UK

In a previous publication of the Cell in 2018 (10.1016/j.cell.2018.01.021), the Errington team had demonstrated that the human immune system can also to some extent induce L-form switching but administration of antibiotics have a much more profound effect. The new study showed that L-forms of several bacterial species typically associated with UTIs like E. coli, Enterococcus, Enterobacter, and Staphylococcus were noticeable in 29 out of 30 patients involved in the study.

In this L-form the bacteria are flimsy and weaker but some manage to survive, hiding inside the body.

The research also succeeded in capturing on video for the first time, L-form bacteria which was isolated from a patient with UTI re-forming a cell wall after the antibiotic had gone, in just 5 hours.

The team was also able to demonstrate by direct microscopy in the transparent zebrafish model, that the L-form switching is possible in whole living organism and not just in artificial conditions in the lab.

Dr. Mickiewicz explained, “In a healthy patient this would probably mean that the L-form bacteria left would be destroyed by their hosts’ immune system. But in a weakened or elderly patient, like in our samples, the L-form bacteria can survive. They can then re-form their cell wall and the patient is yet again faced with another infection. And this may well be one of the main reasons why we see people with recurring UTIs. For doctors this may mean considering a combination treatment—so an antibiotic that attacks the cell wall then a different type for any hidden L-form bacteria, so one that targets the RNA or DNA inside or even the surrounding membrane.”

The research also revealed that L-form bacteria is hard to identify using traditional methods available in a hospital as the gel used in effect “pops” the bacteria when they are put into it.

A special osmoprotective detection method was required to support the weaker L-form bacteria, aiding them to get  identified in the lab.

The team will continue their research with trials in patients who have had treatment.


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