December 9, 2022

How fast-growing bacteria can resist antibiotics

Scientists have demonstrated how certain fast-growing bacteria can retreat with antibiotics, according to a study published today in eLife.

The results show that rapidly growing individuals within bacterial colonies display significantly higher expression of active ribosomes – particles within the cell that synthesize proteins. This helps bacteria avoid the buildup of an important class of antibiotics called macrolides and therefore resist therapy. These findings could be used to inform the development of improved antibiotic compounds that target this survival strategy.

Bacterial infections can cause food poisoning, pneumonia, sepsis, and other serious illnesses. Although they can be treated with antibiotics, the overuse of these drugs in recent years has meant that bacteria are becoming increasingly resistant to them, posing a significant threat to global health.

For an antibiotic to be effective against infection, it must reach its cellular target in sufficient concentration to inhibit bacterial growth.

“Antibiotic resistance continues to threaten the viability of current treatments. We need to understand how individual bacteria within a colony can block antibiotics from entering their cells, so that we can target this mechanism with new therapies,” says Urszula Łapińska, PDRA at the university. from Exeter, UK. “Most of the existing data on drug permeability in bacteria have been obtained through measurements that take an average result from a large population or are derived from a small number of bacteria. This means that little is known much about the variability of individual drug accumulation in many cells in a bacterial colony.

To fill this gap, Łapińska and the team began by hypothesizing that variations in how bacteria respond to drugs might be driven by the varying rates of drug transport between individual cells. To test this, the team used a multi-analytical approach, combining microfluidics-microscopy, which bacteria pose a health threat – namely Escherichia coli, Pseudomonas aeruginosa, Burkholderia cenocepacia and Staphylococcus aureus and antibiotic-derived fluorescent probes by Dr Mark Blaskovich of the University of Queensland. This approach allowed the team to examine the interactions between common antibiotics and many individual live bacteria in real time, during drug dosing. By combining this approach with mathematical modeling techniques developed by Professor Krasimira Tsaneva-Atanasova of the University of Exeter, the team obtained data that they could use to quickly and efficiently identify individual bacteria resistant to antibiotics.

Their analyzes demonstrated that rapidly growing individuals within a colony avoid the accumulation of macrolides in their cells – a finding that contrasts with current thinking that slow cell growth is the primary contributor to antibiotic-free survival. genetic variation. This avoidance is made possible by a significantly higher amount of ribosomes before drug treatment, compared to individuals’ slow-growing counterparts. Ribosomes activate essential cellular processes, including efflux – a system that pumps toxic substances, such as antimicrobial compounds, out of the cell.

Using this new knowledge, the researchers then showed that chemical manipulation of the outer membrane of bacterial cells can eradicate fast-growing variants that exhibit low macrolide accumulation, thus contributing to our fight against antibiotic resistance.

“This work reveals a hitherto unrecognized survival strategy in some members of bacterial colonies,” concludes Dr Stefano Pagliara, senior lecturer in microfluidics at the University of Exeter, UK. “This knowledge will directly benefit microbiologists and clinicians working to develop more effective antibiotic therapies. In the longer term, we hope that the use of our new approach in the clinical setting will help inform the design of improved drugs and help us in the fight against antibiotic resistance.”

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Materials provided by eLife. Note: Content may be edited for style and length.