New drug tested on mice could be used to treat human infections that no longer respond to routine antibiotics, say scientists

The discovery of a new class of antibiotics that can wipe out persistent infections of the hospital superbug MRSA has raised fresh hopes for progress in the fight against antimicrobial resistance.

Health officials around the world have seen a steady rise in bacterial infections that no longer respond to routine antibiotics. With resistance emerging faster than new drugs can be developed, the World Health Organisation (WHO) has called for urgent action to combat the problem.



Last year, England’s chief medical officer, Dame Sally Davies, warned that antibiotic resistance could spell “the end of modern medicine”, with routine operations becoming impossible because doctors run out of antibiotics to keep common infections at bay.



In the latest research, US scientists focused on a small but important group of recurrent infections, which are driven by bacteria that evade antibiotics by lying dormant in the body. The infections tend to affect people with medical implants, or with particular conditions such as cystic fibrosis.



Led by a team at Rhode Island Hospital in Providence, the scientists tested the effects of 82,000 lab-made molecules on roundworms infected with MRSA, or methicillin-resistant Staphylococcus aureus. From the 185 compounds that showed some effect, they selected two of the most promising for further attention. Both belonged to a family of molecules known as retinoids, which were originally developed in the 1960s to treat acne and cancer. They are chemically similar to vitamin A.

Tests on the two retinoids, combined with computer modelling, showed that the compounds killed not only normal MRSA cells, but dormant, or “persister”, cells too. The drugs worked by making the membranes that surround the bacteria more leaky. The same effect explained why the retinoids worked even better when used in tandem with an existing antibiotic called gentamicin.

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There was, however, a downside. The drugs were not effective against an entire group of harmful bacteria for which new antibiotics are badly needed. Responsible for urinary tract infections, stomach bugs, gonorrhoea, pneumonia and the plague, among other diseases, these include Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Klebsiella pneumoniae and Yersinia pestis.

However, the drugs still hold promise for treating persistent MRSA infections that can be lethal for patients affected. Writing in the journal Nature, the scientists describe how they tweaked one of the retinoid compounds to make it less toxic, and then injected it into a mouse with what would generally be considered to be a treatment-resistant MRSA infection. The drug not only cleared the infection, but did so without causing any apparent side-effects, the authors note.

The lead scientist on the study, Eleftherios Mylonakis, whose mother died from a drug-resistant hospital infection, said the drug was some years away from human trials, but added: “The hope is that we are a step closer to finding a treatment for the most difficult bacteria. The MRSA persisters are resistant to antibiotics and MRSA is both common and very virulent.”



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The rise of drug-resistant infections is a direct consequence of evolution. When people or animals are given antibiotics, some of the bacteria the drugs are meant to kill may survive because they have chance mutations that protect them. Over many microbial generations, these mutations become more dominant and the bacteria more resistant, meaning new drugs are needed to wipe them out. To make matters worse, bacteria of different species can swap protective genes with one another.



To combat the spread of antibiotic resistance, doctors and farmers have been urged to use antibiotics far more sparingly than in the past, but this week a separate research team revealed that antibiotic use worldwide has increased by more than 65% since 2000.

In an article accompanying Mylonakis’s study, Julian Hurdle and Aditi Deshpande who study antibiotic resistance at Texas A&M Health Science Center in Houston, wrote that, in an era when the development of antibiotics is struggling to keep pace with the spread of resistant bacteria, the identification of the drugs “could help researchers to win victories in the long fight against bacterial infectious diseases”.