An end-around to defeat resistant bacteria

Imperial College London researchers devise 'decoy' drug to deal with difficult infections

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LONDON—Bacteria have learned to use evolution—and often biological trickery related to their evolutionary adaptations—to get around the human immune system’s defenses and even the antibiotic drugs designed to kill those bacteria. So, if trickery is going to be used, why not use some trickery ourselves?
And that is precisely what researchers at Imperial College London decided to do when they devised a new type of “decoy” drug to tackle infections that are resistant to antibiotics. As a news article by Hayley Dunning at Imperial College London’s website notes, “In lab tests on bacterial cultures, the new drug successfully killed a strain of drug-resistant bacteria. It works by delivering two antibiotics, one of which is effectively hidden. When the bacteria fight against the first ‘decoy’ antibiotic, this action opens up the drug, triggering the second antibiotic into action.”
Essentially, this makes it possible for the delivery of the second antibiotic to take place in a more targeted manner so that it only comes out onto the immunological battlefield at a point where it will encounter drug-resistant bacteria. The researchers believe this could help prolong the life of existing antibiotics by slowing the rate at which bacteria become resistant to them.
The results of the research were published in the paper “Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug,” which appeared recently in the Journal of Medicinal Chemistry.
Dunning wrote further: “A wide range of bacteria, including E. coli, have evolved a special enzyme that can cleave (split) frontline antibiotics known as cephalosporins, rendering them useless. To get around this, the team attached a cephalosporin molecule to a secondary antibiotic called ciprofloxacin.
“When resistant bacteria encounter the combined drug they cleave the cephalosporin, setting the ciprofloxacin free to kill the bacteria. Ciprofloxacin is rarely used as a primary treatment for infections because it can have severe side effects. However, since it is only activated when the cephalosporin is cleaved, the levels in the bloodstream are much lower and will hopefully lead to fewer side effects.”
Put more technically, the researchers write in the abstract for their paper: “Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.”
Notes Dr. Thomas Webb, co-author of the paper: “No matter how good bacteria are at evolving resistance to antibiotics they can never ‘think ahead,’ and this is why we believe setting a trap for them in this way may be so effective.”
The researchers also believe the more targeted use of antibiotics will cause less disruption of the beneficial microorganisms in the human microbiome. Further, they note that this decoy approach is attractive because getting rid of antibiotic-resistant bacteria is especially important when patients have repeat infections, given the likelihood that such resistant bacteria are hiding in the body between symptomatic episodes.
“For example, urinary tract infections, some of the most common infections in the world, are often caused by resistant bacterial populations persisting in the body,” Dunning wrote. “Clearing the body of resistant bacteria would also be useful prior to surgery or chemotherapy, to prevent opportunistic infections while the body’s immune system is compromised.”
The team has applied for a patent on this decoy drug and are looking to expand the concept to other antibiotics.
“Given the lack of new drugs in the pipeline it’s essential to develop new ways of using the existing stock of effective medicines to function in new ways, to reduce their damaging effects on our resident ‘good bacteria’ and to slow the rate at which bacteria become resistant to them,” observed lead researcher Dr. Andrew Edwards of the MRC Centre for Molecular Bacteriology and Infection at Imperial College London.
As the authors conclude in their paper, “In summary, this study paves the way for the development and use of small molecule therapeutics that selectively target drug-resistant pathogens using broad-spectrum antibiotics while minimizing selection for resistance and without collateral damage to the microbiota. This complements ongoing efforts to alter the spectrum of activity of existing antibiotics to enable them to be used in new ways.”

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