Fertility drug shows promise for combatting antibiotic resistance
Despite strenuous efforts to combat the bacterium Streptococcus pneumoniae, the pathogen remains serious threat to human health, particularly among young children. Every year, 14 million under-5s suffer serious illness as a result of infection, and more than 800 000 children are killed. Although S. pneumoniae can be treated with penicillin-based drugs like amoxicillin, resistant strains are increasingly common. The project GetToKnowPneumo received funding under the Marie Skłodowska-Curie Actions programme to uncover new insights into the cell biology of the bacterium. Fellow Liselot Dewachter at the University of Lausanne in Switzerland outlines the hopes of the project: “As well as gaining cell cycle details, we were hoping that we would be able to translate our results into practical applications that can be used in the clinic.”
Why shape matters
Knowing that the development of novel antibiotics can take more than a decade, the researchers aimed to identify drugs which could boost the antimicrobial activity of existing antibiotics. Combining two drugs that target the same process can create a synergistic effect, with the combination stronger than the sum of the individual compounds. Since amoxicillin works by disrupting the growth and division of bacterial cells, the team used CRISPR interference to identify genes responsible for maintaining proper cell size. “CRISPR interference is a modified version of CRISPR where the DNA is not cut, but the expression of genes that are targeted by the CRISPR interference system is inhibited,” Dewachter explains. The researchers then used fluorescence-activated cell sorting to screen individual cells for characteristics of interest – in this case, changes to the cell structure. “This bacterium usually has an oval shape that looks like a rugby ball. However, we have found that they can become very long rods when some proteins are depleted,” says Dewachter. Her team showed that this phenotype was caused by insufficient transport of cell wall precursors across the cell membrane, due to inhibition of undecaprenyl phosphate (Und-P), the lipid carrier responsible for this process.
Old drug, new use
With this information, the team identified the fertility drug clomiphene as a candidate for combination therapy with amoxicillin. The FDA-approved medication is an inhibitor of Und-P synthesis. In the lab, a combined treatment made drug-resistant S. pneumoniae sensitive again to clinically relevant concentrations of amoxicillin. If these results hold true for human infections, this approach can be used to effectively revert resistance and extend the clinical lifespan of our current antibiotic arsenal. Currently, a manuscript is in preparation to be finished in the coming months. The project results were presented pre-COVID at the conference ‘Bacterial Morphogenesis, Survival and Virulence: Regulation in 4D’ in 2019 in South Africa. “Even though the funding of the project has ended, we are still pursuing this research line to completion,” notes Dewachter. Currently, in vivo tests are being performed by collaborators to test the clinical potential of this novel treatment strategy. “Additionally, we are looking into the possibility of applying for a patent to hopefully translate them to the clinic.”
Keywords
GetToKnowPneumo, bacteria, antibiotics, resistance, S. pneumoniae, CRISPR interference