Collaborations are key to tackling antimicrobial resistance

Professor Chris Schofield FRSC FRS, University of Oxford

Antibiotic resistance has taken centre stage recently. About time, too, say many who have persevered in the field in the years when it wasn’t fashionable or significantly funded. However, if we want to maintain interest for the time it takes to introduce new medicines, we must put in place long-term plans now.

A global crisis

Antibiotic resistance is not new: penicillin resistance was identified in the 1940s. However, the pharmaceutical industry was once exceptionally efficient at addressing it. In many ways, the industry was a victim of its own success – antibiotics worked so well most of the time and were so cheap that the motivation for innovation and investment were tempered to the extent that the supply of new antibiotic types dried up.

Today, antibiotic resistance has reached crisis levels in several parts of the world and there is global concern that resistance may become so biologically embedded that major classes of antibiotics may no longer work. Long-term solutions to the resistance problem will ultimately involve global controls over antibiotic use. But in reality, introducing such controls will be time-consuming, and policing them anything but trivial. So governments and funding agencies must be encouraged to think about what we do in a scenario in which one or more classes of antibiotics become useless. 

Combining expertise

Despite the advent of molecular biology and genetic engineering few – if any – new clinically validated antibiotic targets have emerged in recent years. To what extent this reflects a lack of focus on antibiotic research and development unknown. Nonetheless, it would appear that there have been few large-scale contemporary medicinal chemistry efforts on antibiotics that match, for example, the manner in which kinases have been targeted to develop anti-cancer treatments.

Yet our methods and knowledge have advanced significantly since the ‘golden age’ of antibiotics. We now have detailed structural insight into bacterial cell walls and the protein biosynthesis machinery, while molecular biology and proteomics have enabled us to screen against isolated proteins and in cells.

Synthetic methods, especially asymmetric catalysis, hold promise for generating natural-product-like compounds, which are the basis of most antibiotics, and rational biosynthetic engineering will be of use in generating structurally complex and synthetically inaccessible antibiotics. In short, the underpinning research scene is well set for the discovery of new antibiotics.

Appropriate support required

Pharmaceutical companies might be encouraged to focus on antibiotics by the increasing resistance problems and by advances in diagnostics that will enable targeting of specific bacteria. However, this is no certainty, so there is strong case for public efforts in the antibiotic arena. But we can’t forget that medicinal chemistry is expensive and challenging – particularly so in the antibiotics field, where demanding and highly-efficient synthesis is often required.

One of the problems is that, in Europe, there is a strong academic commitment to antibiotic research, but the clinical demand is not yet at the same crisis level as in some parts of the world. One possibility is for European scientists to link better with their counterparts in parts of the world where resistance is already a major issue. Intellectual property issues concerning specific compounds have, in the past, posed a constraint to such collaborations, but many antibiotics are now generic, and companies can make profits in antibiotics without patent protection. The bottom line is that we need to find ways of bringing multiple laboratories  together while minimising legal and administrative barriers that are sometimes associated with collaborative research.

Looking beyond antibiotics

We also mustn’t forget that biological resistance is a much wider issue. Resistance to other types of antimicrobials, antivirals, anti-tumour agents and other pharmaceuticals is also of major medical importance. And resistance to pesticides and herbicides threatens existing agriculture with potentially disastrous consequences for food production.

At the scientific level, defining the differences and similarities in the chemical mechanisms that enable resistance in different biological contexts is of interest. It would seem unlikely that, in the short-term, a single field will deliver major advances. Work in the resistance field needs to be truly interdisciplinary, ranging from human population science to microbiology, and there is evidence that studying the chemistry behind resistance will be fruitful. For example, we already know that related types of enzymes and efflux pumps are involved in resistance to some antibiotics and anti-cancer agents.

Chemists have a role to play

In addition to collaborating on tackling the resistance problem, we also need to speak up publically to ensure funding decisions are not made without the chemistry’s input. New antibiotics simply won’t happen without a critical mass of high-quality synthetic chemistry that is closely linked to microbiology and helped along by the more modern tools of drug discovery.

From an organic chemistry perspective, many antimicrobial natural products are wondrous structures with remarkable mechanisms of action. Working on the chemistry required to develop new antibiotics is already immensely attractive. And working in an internationally coordinated manner that combines strengths in synthetic chemistry, modern structural, molecular and microbiology with expertise in medicinal chemistry may accelerate the discovery of the next penicillin.