The prevalence of antibiotic-resistant bacteria has rapidly increased in recent years and it is threatening to become one of the leading causes of death in the near future. The actual frequency of untreatable infections is so high that last year, the World Health Organization (WHO) published a list of multi-drug resistant bacteria that should be the first priorities for research and the discovery and development of new antibiotics. A wide set of public campaigns have also been launched to increase people’s awareness about antibiotic resistance and establish good-practices regarding human and veterinary antibiotic usage.
For several years now, our group has been studying how bacterial resistance to antibiotics evolves under laboratory conditions and how adaptation to a given antibiotic implicates bacterial resistance to other antibiotics. Together with the work of others, it has become clear that the evolution of resistance towards antibiotics, or any other drug, can simultaneously increase (cross-resistance) or decrease (collateral sensitivity) bacterial fitness to multiple other drugs. While the mechanisms of multi-drug resistance have been thoroughly studied, the mechanisms leading to collateral sensitivity are still poorly understood, eventhough this is a crucial point in the development of new antibacterial drugs. Studying collateral sensitivity interactions between drugs can help to establish efficient drug-cycling or combination therapies against multi-drug resistant superbugs. The application of a collateral sensitive drug pair may also reduce the chances of the appearance and spread of novel resistance mechanisms.
We decided to focus our recent studies on a relatively new class of antimicrobial agents known as antimicrobial peptides. Antimicrobial peptides are found among all classes of life as part of the defense mechanisms against microbial pathogens. They are known to have a broad spectrum of antibacterial activities and very diverse modes of action. But can we effectively use antimicrobial peptides to treat antibiotic-resistant infections?
We used a group of 60 antibiotic-resistant bacterial strains which were previously well characterized in our lab to reveal their mutations as well as their resistance and sensitivity to other antibiotics. Now, we measured their resistance and sensitivity towards 24 antimicrobial peptides and found that cross-resistance to antimicrobial peptides is much less frequent than to conventional antibiotics, while collateral sensitivity was widespread. Besides identifying possible mechanisms leading to collateral sensitivity to antimicrobial peptides, we were able to show that utilizing collaterally sensitive combinations of antibiotics and antimicrobial peptides could reduce the amount of antibiotic needed to kill such antibiotic-resistant bacteria, as well as slowing down the emergence of antibiotic resistance during treatment.
Needless to say, this proof-of-concept study needs to be followed up further. Close cooperation between microbiologists and medicinal chemists is needed to improve stability and activity of antimicrobial peptides so that they can be suitable for clinical usage. Nevertheless, we show that antimicrobial peptides are a diverse and promising group of molecules, and identify possible leads with great potential for further development.
Read the full paper here: https://go.nature.com/2kwHEY1
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