Biotechnology

Swedish bacterial resistance study points to a new antibiotic

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A species of common gut bacteria multiplies when the gut flora is destroyed by antibiotics. Since bacteria are naturally resistant to many antibiotics, this can create problems.

A study at Lund University in Sweden now shows how two molecular mechanisms can work together to make bacteria more resistant.

“Using this knowledge, we hope to design even better drugs,” said Vasili Hauryliuk, a senior lecturer at Lund University, who led the research.

The threat from antibiotic-resistant bacteria is well known and serious. Last year, The Lancet reported that around 1.27 million people died in 2019 from bacterial infections that couldn’t be treated with existing medicines. To address this, it is important to understand the underlying molecular mechanisms.

During antibiotic treatment, the normal gut flora is disrupted, which provides an opportunity for antibiotic-resistant pathogens to be suppressed despite competition with “good” gut bacteria. One of the most problematic species of bacteria is Clostridioides is difficultformerly known as Clostridium difficile or, more commonly, C. diff.

It is found in the intestines, is resistant to antibiotic treatment and can cause serious diarrheal infections. The bacteria’s ability to make spores means it can spread easily and therefore cause problems in healthcare settings, resulting in increased deaths and longer treatment times.

“Instead of antibiotics saving you, in this case it actually triggers a secondary bacterial infection,” said Hauryliuk.

New proteins

“The risk of C. diff infection is known to increase after treatment with an antibiotic called clindamycin, but the reason is unknown. Our research shows the new protein confers resistance to the class of antibiotics included in clindamycin,” said Obana Nozomu, assistant professor at the University of Tsukuba and one of the researchers behind the study.

The resistance mechanisms of C. diff have been investigated by an international collaboration between researchers in Sweden, Japan, UK, US, Estonia and Germany, and the results of these studies were published in Nucleic Acids Research.

The researchers identified a new protein responsible for resistance. Proteins act on ribosomes – the molecular factories that produce proteins in bacteria. Ribosomes are one of the main targets of antibiotics: if proteins cannot be synthesized, bacteria will not grow, replicate and cause infection.

“This newly discovered protein secretes an antibiotic molecule from the ribosome. We also see that it is coupled with other resistance factors. The second chemically modifies the ribosome so that the antibiotic molecule binds to it less tightly. The extra strong resistance is the result of two mechanisms, two factors, which combine and, in so doing, give bacteria a ‘super power’ against antibiotics,” said Gemma C. Atkinson, senior lecturer at Lund University and co-author of the article.

New treatment potential

The researchers used cryogenic electron microscopy to study the mechanisms of resistance to antibiotics at the molecular level. This knowledge paved the way for new treatment strategies against resistance and infections caused by bacteria.

“Several years ago, Andrew G. Myers’ laboratory at Harvard University developed a new generation of ribosome-binding antibiotics, known as iboxamycin. This is a very potent drug that inactivates ‘ordinary’ C. diff bacteria. However, the results of this study indicate that C. diff strains that share both resistance factors are, unfortunately, also resistant to this antibiotic. This means it is necessary to design antibiotic molecules that bind more strongly to defeat this kind of resistance,” said Hauryliuk, adding that they will now collaborate with Myers’ group on future studies.

Research has also found that certain antibiotics that target the ribosome induce the production of resistance factors. It may also provide clues for designing new antibiotic molecules, as resistance cannot be induced if resistance factors are not synthesized.

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