C. diff's powers of antibiotic resistance revealed

A species of ordinary gut bacteria that we all carry flourishes when the intestinal flora is knocked out by a course of antibiotics, which can cause problems — particularly in healthcare settings. An international team of researchers, led by Lund University, has now revealed how two molecular mechanisms work together to make the bacterium extra resistant.

The researchers hope that their results, which have been published in the journal Nucleic Acids Research, can be used to design better and more effective medicines.

The threat posed by antibiotic-resistant bacteria is well known — according to The Lancet, an estimated 1.27 million people died in 2019 as a result of bacterial infection that could not be treated with existing medicines. In order to tackle this threat, it is essential to understand the underpinning molecular mechanisms.

During antibiotic treatment, the normal intestinal flora is disturbed, which provides an opportunity for antibiotic-resistant bacterial pathogens that are otherwise suppressed through competition with ‘good’ gut bacteria. One of the most problematic bacterial species is Clostridioides difficile, which is found in our intestines, is resistant to antibiotic treatments and can cause serious diarrhoeal infections. The bacteria’s ability to create spores means it is easily spread and therefore causes problems in healthcare settings, resulting both in increased mortality and extended treatment times.

“The risk of infection with C. diff is known to increase after treatment with an antibiotic called clindamycin, but the reason for this was unknown,” said Obana Nozomu, an assistant professor at the University of Tsukuba. “Our research showed a novel protein conveys resistance to the class of antibiotics to which clindamycin belong.”

“Instead of the antibiotic saving you, in this case it promotes a secondary bacterial infection,” added study leader Vasili Hauryliuk, a senior lecturer at Lund University.

The novel protein works on the ribosome — the molecular factory that produces the proteins in the bacteria, and which gives the bacteria its abilities. The ribosome is one of the primary antibiotic targets: if proteins cannot be synthesised, the bacteria will not grow, replicate and cause the infection.

“This newly discovered protein kicks the antibiotic molecule out of the ribosome,” said study co-author Gemma C Atkinson, a senior lecturer at Lund University. “We also saw that it combines with another resistance factor. The second chemically modifies the ribosome so that the antibiotic molecules bind less tightly to it. The extra-potent resistance is the result of two mechanisms, two factors, which combine and in so doing give the bacteria its ‘superpowers’ against antibiotics.”

The researchers used cryogenic electron microscopy in order to study the resistance mechanisms against antibiotics on a molecular level. This knowledge opens the way for new treatment strategies against resistance and the infections that the bacteria cause.

“A couple of years ago, Andrew G Myers’ lab at Harvard University developed a new generation of ribosome-binding antibiotics, known as iboxamycin; it is a very potent medicine that knocks out ‘ordinary’ C. diff bacteria,” Hauryliuk said. “The results of this study, however, show that C. diff strains that have both resistance factors are, unfortunately, resistant to this antibiotic as well. This means that it is necessary to design antibiotic molecules that bind even tighter in order to overpower this kind of resistance. We now collaborate with the Myers group on this direction.”

This study also found that certain antibiotics that target the ribosome induce the production of the resistance factor. This may also provide clues for designing new antibiotic molecules, since resistance cannot be induced if resistance factors are not synthesised.

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