Antimicrobial Resistance: putting another brick in the wall

Antimicrobial resistance (AMR) is recognised as a major public health threat.

The ability of human pathogenic bacteria to resist the action of antibiotics is inevitable; however, it has been exacerbated by the overuse and misuse of antibiotics and this has led to our existing armoury of antibiotics becoming less effective.

Antibiotic resistance threatens to undermine progress in the fight against tuberculosis (TB). TB, which is caused by the bacterium Mycobacterium tuberculosis, kills 1.5 million people each year and in recent years it has been increasing due, in part, to rising AMR and decreasing efficacy of vaccines.

Historically, big pharmaceutical companies have been relied upon to develop new antibiotics. However, due to the poor economic return very few new, effective antibiotics have been brought to the market in the past 30 years.

Urgent action is now needed to deal with this crisis, particularly as the timeline for bringing a new antibiotic into the clinic is usually around 10-15 years.

Despite the urgent need for new antimicrobials, very few new, effective antibiotics have been brought to the market in the last 30 years.

The discovery of novel antimicrobials cannot be solved by any one company or institution, it requires large pan-continental consortia to work together.

Large pan-continental AMR consortia such as, MM4TB and ENABLE, attempt to address this crisis. Their aim is to develop attractive antimicrobial candidates for testing in the clinic, bringing the possibility of new antibiotics closer to patients.

Researchers at the John Innes Centre play a small but crucial role in these consortia. One such consortium that we have been a part of, More Medicines for Tuberculosis (MM4TB), have successfully delivered anti-TB compounds into clinical trials. Another consortium, ENABLE has delivered a compound active against Gram-negative bacteria to clinical trials.

Underpinning research

Professor Tony Maxwell’s lab investigates the structure and mechanism of DNA topoisomerases and associated proteins. DNA topoisomerases are vitally important enzymes involved in the control of the topological state of DNA.

The study of DNA topoisomerases has clinical relevance from the standpoint of antibacterial and anti-tumour drugs. For example, DNA gyrase, the enzyme from bacteria that carries out DNA supercoiling, is the target for clinically-important antibiotics, such as the fluoroquinolones.

Tony Maxwell: “My interest in AMR has grown out of a fundamental interest in enzymes, what they do and how they do it; it turns out that some of these enzymes are important in AMR research”.

The AMR consortia consist of many members, some are compound providers, groups whose compounds have be validated in some way, and others target providers, that have druggable targets.

The Maxwell lab are target providers. When it’s suspected that a compound, or group of compounds, hits DNA gyrase, they will be brought in. They will do biochemistry and crystallography studies to determine how these compounds work and feed the information, iteratively back into the consortia to help build new compounds.

“Our role represents a very small slice of a very large cake. No one lab or small group of labs can do this. Having a multicomponent approach is absolutely vital.” explains Tony.

MM4TB finished in 2016 but, following the consortiums work, a number of compounds (e.g. PBTZ169 – macozinone) have entered clinical trials. ENABLE is ongoing and has already progressed one compound active against Gram-negative bacteria (apramycin) to clinical trials. This would not have been possible without a pan-European collaboration.

In addition, the consortia generate lots of interesting research into potential future antibiotics.

AMR is a continuous battle. Going forward, Tony Maxwell would like to see a publicly- funded drug pipeline that brings together all the appropriate skills and provides an adequate pipeline of novel antibiotics to address the challenge of AMR.

“I have been worried about an AMR pandemic for a while, COVID might be the dress rehearsal for that. Ultimately what we are doing is putting ‘another brick in the wall’, but it’s an important brick and a very important wall. The impact is also outputs, i.e. publications and news stories, telling the world what we’ve done; others may be able to use this research and do something a bit better.”