Bacteria less able to develop resistance to antibiotic combinations

Disease and treatment 5. sep 2021 2 min Team Coordinator Leonie Johanna Jahn Written by Kristian Sjøgren

The world increasingly needs to determine how to tackle the crisis of antimicrobial resistance. New research in Denmark shows how combining antibiotics makes resistance more difficult for bacteria.

For the past 18 months, the whole world has been preoccupied with COVID-19 and how to protect ourselves from it.

The pandemic has had major effects on global health. However, looming on the horizon is an even greater crisis: antimicrobial resistance.

Pathogenic bacteria are becoming increasingly resistant to antibiotics, and since novel antibiotics are not being developed as rapidly as resistance is developing, we may end up not being able to overcome simple infections such as urinary tract infections or pneumonia.

The result can be thousands of deaths from infections that can successfully be treated today but may soon become problematic.

However, a new study in Denmark now reveals light at the end of the tunnel. By combining antibiotics, bacteria are less able to develop resistance.

“The problem is that bacteria develop antimicrobial resistance very rapidly, so we have to determine how to best use our antibiotics to slow the evolutionary adaptations of bacteria and thereby limit resistance. Our research identifies how we can combine antibiotics to do this,” explains an author behind the new study, Leonie Johanna Jahn, Team Coordinator, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.

The research has been published in Molecular Biology and Evolution.

Combining antibiotics can be both harmful and beneficial

The reason for combining two antibiotics is that the overall effect may differ from that of the two antibiotics separately.

However, the outcome cannot be predicted because drug combinations vary substantially.

Antibiotic combinations can kill bacteria faster, but that does not necessarily mean that the bacteria develop resistance more slowly. Further, some antibiotic combinations may act less powerfully in combination than their constituent parts.

Another possibility is that bacteria that are resistant to one antibiotic can also rapidly develop resistance to another antibiotic. Conversely, if a bacterium is resistant to one antibiotic, using another antibiotic may be beneficial, since initially developing resistance to the first antibiotic may make developing resistance to the second antibiotic difficult.

“Many factors and combinations have effects about which we know little today. We therefore tried to discover how to combine different types of antibiotics to decelerate the evolution of resistance among bacteria,” says Leonie Johanna Jahn.

Evolution experiment with 22 antibiotics in 33 antibiotic pairs

Leonie Johanna Jahn and colleagues performed a large-scale laboratory experiment with eight strains of Escherichia coli bacteria, which they exposed to 22 antibiotics from 11 drug classes and 33 antibiotic pairs.

The researchers then allowed the bacteria to develop for many generations to develop resistance to the single antibiotics and combinations of antibiotics to which they were exposed.

The researchers then analysed the bacteria’s DNA to elucidate how they had adapted their genetic material to be resistant and how rapidly they had done this.

“In general, the bacteria developed resistance more slowly when exposed to combinations of antibiotics. But we would like to formulate some rules for how to combine antibiotics optimally to prevent the bacteria from developing resistance,” explains Leonie Johanna Jahn.

Genes determine how rapidly bacteria develop resistance

By reviewing the mutations the bacteria made to become resistant to various types of antibiotics, Leonie Johanna Jahn and colleagues determined that some mutations excluded others.

Thus, when a bacterium develops resistance to one antibiotic, the resistance mechanism might be incompatible with other types of antibiotics. Combining these two antibiotics as a treatment option is therefore relevant.

The researchers also found that some combinations caused the bacteria to develop resistance more slowly.

Conversely, the researchers also found that some combinations did not induce the bacteria to develop new resistance mutations, and they rapidly developed resistance.

Broadly speaking, Leonie Johanna Jahn says that forcing the bacteria to evolutionarily develop completely new forms of resistance resulted in slow resistance development. However, if the bacteria could reuse the resistance to one antibiotic to develop resistance to another antibiotic, the process went much faster.

“Different combinations result in different outcomes, and our data support investigating the effects of combination therapy to limit the opportunities to develop resistance. We need to do this for all combinations of antibiotics and for all the bacteria for which the antibiotic combinations are intended. This will provide us with new tools to combat the development of antimicrobial resistance globally,” concludes Leonie Johanna Jahn.

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