The first direct evidence that bacteria living inside us change shape to avoid antibiotics

Today, antibiotic-resistant bacteria are one of the greatest threats to the health of all mankind, which is blamed on the excessive and indiscriminate use of antibiotics. Not only does antibiotic resistance cause about 700,000 deaths a year, but many infectious diseases, such as pneumonia, tuberculosis and gonorrhea, have become much more difficult to treat. Unless we find a way to prevent bacteria from developing antibiotic resistance, it is predicted that preventable diseases could cause 10 million deaths per year by 2050. One way bacteria acquire resistance to antibiotics is by changing their genome. For example, a bacterium can 'pump' an antibiotic out of itself, or break it down in some way. Also, bacteria can stop growing and dividing, making it difficult for the immune system to recognize them.

 

But the researchers turned their attention to another, lesser-known method that bacteria use to develop resistance. We have directly shown that bacteria can 'change their shape' in our body and thus avoid antibiotics - this is the process by which they continue to grow without genetic changes. All bacteria are surrounded by a structure we call a cell wall. It is like tight clothing that protects the bacteria from the environment and prevents it from breaking. The wall gives the bacterium an appropriate shape (for example, like a stick or ball) and helps it to divide successfully.

Human cells do not have a cell wall; because of this, our immune system more easily recognizes the bacterium as an enemy, because its wall is significantly different. This is precisely why bacteria become easy targets for our best and most commonly used antibiotics, such as penicillin. So, antibiotics 'target' the wall and kill the bacteria without danger to us.

But bacteria sometimes live without a cell wall. If the surrounding conditions are suitable for the bacterium not to burst, it can change its shape into a so-called L-form; it is the form in which the bacterium no longer has a cell wall. Such bacteria were discovered by Emmy Kleineberger-Nobel in 1935 and named after the Lister Institute, where she worked at the time. In order to create a suitable protective environment, we often use sugar in the laboratory. In the human body, the bacterial wall is a target for antibiotics, which are thus triggers for changing the bacterial form; the initiators can also be some molecules of the immune system, such as lysozyme - a molecule found in our tears that protects us from bacterial infections.

Without a cell wall, bacteria usually become sensitive and lose their normal appearance. However, it also becomes partially invisible to our immune system and completely resistant to all types of antibiotics that destroy the cell wall in a targeted manner.

Scientists have long suspected that L-forms are responsible for repeated infections, because they help bacteria to 'hide' from the immune system and provide resistance to antibiotics. However, it was difficult to find evidence for this, due to the 'elusive' nature of L-forms and the lack of methods to detect them.

 

We observe the change in the shape of the bacteria

Our study, published in Nature Communications, focused on bacterial species associated with recurrent urinary tract infections (UTIs). It has been shown that many different bacterial species (incl E. Coli and enterococci) can really survive in the human body in L-form. We have never proven this before; we discovered these 'hidden' bacteria by using fluorescent probes that recognize bacterial DNA. We examined urine samples of elderly patients with repeated IUT; we propagated them in a Petri dish rich in sugar. This environment protected the bacteria from bursting, and in addition, the bacterial L-form that was found in these samples was isolated.

 

The significance of this study is that it has been shown that antibiotics should be tested in conditions more similar to the human body. Until now, conditions in medical laboratories have not provided sufficient protection for the sensitive L-forms to survive. Before we can fully understand the significance of this L-form of bacterial resistance to antibiotics compared to other forms, additional studies with more patients will be needed. In addition, the role of L-forms in other recurrent infections, such as sepsis or lung infections, will need to be investigated.

So far, scientists dealing with L-forms have encountered many contradictions, but we expect that these new discoveries will stimulate additional efforts regarding these bacterial forms in patient practice. We hope that this will eliminate the dangers that these 'hidden' bacteria pose to our health.

One of the possible options in the fight against antibiotic-resistant infections is the combination of antibiotics that target the cell wall with those that destroy L-forms. The battle against bacteria continues: we develop new strategies to defeat them, and the bacteria respond with their 'tricks' '. Our study reveals that in the constant fight against infectious diseases, one should definitely take into account another way in which bacteria adapt.

Katarzyna Mickiewicz, Newcastle University Research Fellow, Newcastle University.