Widely-available antibiotics could be used in the treatment of ‘superbug’ MRSA
Genomic analysis shows that a significant number of strains are susceptible to penicillin combined with clavulanic acid
Some MRSA infections could be tackled using widely-available antibiotics, suggests new research from an international collaboration led by scientists at the University of Cambridge and the Wellcome Sanger Institute.
Since the discovery of penicillin, the introduction of antibiotics to treat infections has revolutionised medicine and healthcare, saving millions of lives. However, widespread use (and misuse) of the drugs has led some bacteria to develop resistance, making the medicines less effective. With few new antibiotics in development, antibiotic resistance is widely considered a serious threat to the future of modern medicine, raising the spectre of untreatable infections.
One of the most widely used and clinically important groups of antibiotics is the family that includes penicillin and penicillin derivatives. The first type of penicillin resistance occurred when bacteria acquired an enzyme, known as a beta-lactamase, which destroys penicillin. To overcome this, drug manufacturers developed new derivatives of penicillin, such as methicillin, which were resistant to beta-lactamase.
In the escalating arms race, one particular type of bacteria known as Methicillin-resistant Staphylococcus aureus – MRSA – has developed widespread resistance to this class of drugs. MRSA has become a serious problem in hospital- and community-acquired infections, forcing doctors to turn to alternative antibiotics, or a cocktail of different drugs which are often less effective, and raises concerns that even these drugs will in time become ineffective.
In previous research, a team of researchers in Cambridge identified an isolate of MRSA (a sample grown in culture from a patient’s infection) that showed susceptibility to penicillin in combination with clavulanic acid. Clavulanic acid is a beta-lactamase inhibitor, which prevents the beta-lactamase enzyme destroying penicillin; it is already used as a medicine to treat kidney infections during pregnancy.
In a study published today (24 June) in Nature Microbiology, a team of scientists from the UK, Denmark, Germany, Portugal, and USA used genome sequencing technology to identify which genes make MRSA susceptible to this combination of drugs. They identified a number of mutations (changes in the DNA sequence) centred around a protein known as a penicillin-binding protein 2a or PBP2a.
PBP2a is crucial to MRSA strains as it enables them to keep growing in the presence of penicillin and other antibiotics derived from penicillin. Two of these mutations reduced PBP2a expression (the amount of PBP2a produced), while two other mutations increased the ability of penicillin to bind to PBP2a in the presence of clavulanic acid. Overall the effect of these mutations means that a combination of penicillin and clavulanic acid could overcome the resistance to penicillin in a proportion of MRSA strains.
The team then looked at whole genome sequences of a diverse collection of MRSA strains and found that a significant number of strains – including USA300 clone, the dominant strain in the United States – contained both mutations that confer susceptibility. This means that one of the most widespread strains of MRSA-causing infections could be treatable by a combination of drugs already licensed for use.
Using this knowledge, the researchers used a combination of the two drugs to successfully treat MRSA infections in moth larvae and then mice. Their next step will be to conduct the further experimental work required for a clinical trial in humans.
“MRSA and other antibiotic-resistant infections are a major threat to modern medicine and we urgently need to find new ways to tackle them. Developing new medicines is extremely important, but can be a lengthy and expensive process. Our works suggests that already widely-available medicines could be used to treat one of the world’s major strains of MRSA.”
Dr Mark Holmes from the Department of Veterinary Medicine at the University of Cambridge, and a senior author of the study
“This study highlights the importance of genomic surveillance – collecting and sequencing representative collections of bacterial strains. By combining the DNA sequencing data generated by genomic surveillance with laboratory testing of the strains against a broad selection of antibiotics, we may find other unexpected chinks in the armour of antibiotic-resistant bacteria that might give us new treatment options.”
First author Dr Ewan Harrison from the Wellcome Sanger Institute and the University of Cambridge
The research was funded by the Medical Research Council (MRC), Wellcome and the Department of Health.
“This study demonstrates how a mechanistic understanding of resistance and access to clinical data can be used to find new ways to contain and control infections with existing resources.”
Dr Jessica Boname Head of Antimicrobial Resistance at the MRC
Harrison, EM et al. Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus. Nature Microbiology; 24 June 2019; DOI: 10.1038/s41564-019-0471-0
The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 107 affiliates of the University have won the Nobel Prize.
Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.
The University sits at the heart of the ‘Cambridge cluster’, which employs 60,000 people and has in excess of £12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents.
The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation. https://mrc.ukri.org
The Wellcome Sanger Institute is a world-leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science.
Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth.
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