Investigating human metabolites and their response to antibiotics

Researchers at the University of Liverpool are studying human metabolites as indicators of bacterial responses to antibiotics to improve sepsis treatments and address the growing global issue of antimicrobial resistance.

Dr Howbeer Muhamad-Ali and his team from the University of Liverpool’s Institute of Systems, Molecular and Integrative Biology are leading metabolomic research (the study of small molecules within cells, tissues, biofluids or organisms), focussing on how metabolic activity and metabolites respond to antibiotics. They are researching how metabolites respond to antibiotics as an indicator of the success of sepsis treatment, a potentially life-threatening disease. They are also working to improve the effectiveness of antibiotic treatment on biofilms, a major challenge for treating microbial infections and a driver of antimicrobial resistance.

Current sepsis treatment

Sepsis is a very serious illness that is caused by the body’s immune system overreacting to an infection, which damages our organs and tissues. Every year it causes up to six million deaths worldwide, and whilst it can be treated with antibiotics if diagnosed early enough, many sufferers will experience permanent and life-changing impacts.

“I have personal experience of sepsis. My father was very ill with the condition in hospital but luckily he survived, many people are not so fortunate” said Dr Muhamad-Ali. “Currently patients taken to critical care with suspected sepsis are given treatment straight away before the results of microbiological analysis to determine the type of bacteria. Initial antibiotic treatments are usually modified once the results are available, which may lead to an escalation or de-escalation of treatment. However, due to the inherent quality and diverse content of sepsis and lack of gold standard diagnostic techniques, escalation of the antibiotic treatment is usually initiated when clinical deterioration has already occurred.” 

Monitoring treatments through metabolites

Working in partnership with Professors Enitan Carrol at Alder Hey Children’s Hospital and Roy Goodacre of the University of Liverpool’s Centre for Metabolomics Research, Dr Muhamad-Ali and his  team hope to identify metabolites (small molecules) that can be used as biomarkers to monitor clinical improvements in patients, and their response to treatment before deterioration. 

Identifying these markers, or in this case metabolites, may allow for earlier detection of response or lack of response to antibiotics, allowing doctors to change to more appropriate ones before deterioration occurs, ultimately reducing complications and saving lives. Funded by Wellcome ITPA and the University of Liverpool’s Health and Life Sciences Translational Research Access Programme (TRAP Awards) the research will enable preliminary findings over one year to hopefully secure a longer-term grant.

Antimicrobial resistance research

The research builds on the team’s other strand of ongoing work into biofilms, a protective cover that forms on microbiomes and the case of bacteria and can act as a defensive shield against antibiotics. “The emergence and spread of antimicrobial resistance (AMR) is becoming a real threat to human health and biosecurity worldwide, and biofilms are considered the ideal environment for spread and development of AMR,” described Dr Muhamad-Ali. “Biofilms secrete substances (extracellular polymeric substances -EPS) that limit the penetration of drugs into the matrix, which in turn reduces the concentration of the drug to below its effective levels.

“In addition, the barrier nature of EPS also affects the penetration of other molecules and nutrients as well as a build-up of toxic compounds into the biofilm which may trigger a cellular response that slows down metabolic activity of the cells and contributes to the development of persister cells which resist antibiotics treatments. These biological complexes are widely distributed in environmental, medical and industrial settings, and despite the efforts towards combatting biofilm formation they are still responsible for more than 80% of all microbial infections in humans. To combat such a global issue, a deeper understanding of the basis of AMR is essential, covering the microbial response to antimicrobial exposure and adaptive evolution, as well as drug target, penetration and distribution in planktonic cells and community (biofilm) structures.”

Centre for Metabolomics Research (CMR)

Using Raman and infra-red spectroscopy imaging and other analytical techniques, the team can build 3D pictures of how deep antibiotics penetrate biofilms and if they have any effect on the bacteria within. By using isotopic labelling, a technique for tracking a substance through a system, in this case a drug through a bacterial organism, the team can see if the drug is passing through the biofilm and effectively targeted the infection. Such a strategy will also allow for identifying which cells are active with high metabolic activity and those that are effectively dormant with low activity, as changes in metabolism will indicate the effectiveness of the antibiotic. 

The team are currently working with Professor Rasmita Raval, Department of Chemistry and Director of the Surface Science Research Centre and the Open Innovation Hub for Antimicrobial Surfaces at the University of Liverpool, to investigate the metabolic response of bacteria on different engineered surfaces and the effectiveness of certain materials to stop biofilm formation, something that could be beneficial in clinical, and industrial environments. 

Dr Muhamad-Ali, added: “At the Centre for Metabolomics Research (CMR) we have state-of-the -art metabolomics facilities including mass spectrometry and spectroscopy imaging equipment, combined with the all-important multidisciplinary expertise on one site which makes us well-placed to carry out impactful research like this. One of the main advantages of metabolomics is that it is generally employed as a data-driven approach (inductive research), rather than theory-driven science which tries to validate existing theories.”

“This allows us to carry out untargeted analytical research and look into problems that have real impacts on how we live worldwide. Through partnerships with the NHS, pharmaceutical companies and private companies we’re able to work together to find solutions from saving lives to making the production of food and other industrially valuable products more efficient and economical.” 

Anyone interested in collaborating with the Metabolomics team within the Microbiome Innovation Centre or accessing the University’s world-leading equipment can find out more here.

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