Down with the Resistance

From one perspective, antibiotics are a gift from medicine to mankind. But they are a gift with a timebomb. The more widespread their use, the greater the bacterial resistance against them becomes. As every antibiotic is doomed to eventual impotence, the only way to buy time is to mine deeper and discover more. Or is it? New work led by Christopher Schofield, Head of Organic Chemistry at the University of Oxford, points to a tactic that could change the game entirely by sending in a chemical “guardian angel” to defeat resistance itself (1).

What kind of work do you do at the University of Oxford?
 

I came to Oxford for doctoral studies on how penicillins and related drugs work, and how nature makes these remarkable molecules. Attempting to address these questions has taken our group into fields we never anticipated, such as the chemistry of genetics and how human beings sense changes in oxygen availability. However, from a societal perspective, the most important field we work in is antibiotics.

How much should we fear the growing resistance to antibiotics?
 

If we don’t address the resistance problem, the World Health Organization estimates that by 2050, bacterial infections will be responsible for 10 million deaths a year, overtaking the number of cancer related deaths. Routine surgery, such as hip or knee replacements, will no longer be possible because of the risk of bacterial infections. We view our work as a stepping stone towards addressing one of the greatest medical challenges of our time. Perhaps the most important thing we can do is help and inspire others to work in the field.

What is the science behind your work on resistance busters?
 

Like all antibiotics, penicillins (and optimized versions, such as the carbapenems) are subject to resistance, which is now severely compromising their use. A key resistance mechanism involves the destruction of the four-membered ring (known as the beta-lactam ring) that is essential for penicillin drug activity. The resistance reaction involves the addition of water as catalyzed by beta-lactamase enzymes.

Our work has involved the development of β-lactamase inhibitors for use in collaboration with a carbapenem. In effect, the β-lactamase inhibitors act as a guardian angel, protecting the antibiotic from attack by bacterial resistance.

Can you run us through the research behind your guardian angels?

Our project has its origins in basic research into beta-lactamases. Early work identified two specific classes – metal-ion-using-beta-lactamases, known as MBLs, and those that do not use metal ions at all. Inhibitors that neutralize the latter are widely used to protect penicillins, while the MBLs were long considered to be of academic interest only.

However, MBLs are now key agents of resistance, particularly in lower-middle-income countries, though it’s near certain that they will spread globally. To date, no clinically useful MBL inhibitors have been developed. Such drugs could be used to protect beta-lactam antibiotics (including carbapenems, which are often used in last resort situations) from MBL-catalyzed destruction.

To date, MBLs have not been a focus for industry because their spread is not endemic in the developed world. Following on from collaborative European work on the basic science of MBLs, we developed assays for them. Via the Innovative Mechanisms Initiative (IMI), a European Public-Private Partnership, we first ran a high throughput screen aiming to identify new MBL inhibitors. And that led us to a new class of metallo enzyme inhibitor – the indole-carboxylates (InCs), which inhibit all clinically relevant MBLs. The project then transferred to the European Gram-Negative Antibacterial Engine (ENABLE) component of the Innovative Mechanisms Initiative, which aims to make treatments combating antibacterial resistance. The combined efforts of the ENABLE parties across Europe led to the optimization of the initial hit InCs to provide compounds that are highly active in animal models.

Can you tell us more about the level of collaboration needed on this project?
 

Well, this work was only possible through fantastic collaboration, and required the combined efforts of a highly interdisciplinary team! Chemists prepared the various molecules, biochemists studied them against the MBL enzymes, and microbiologists looked at their effects on superbugs. Later, as the project developed, experts who could help with the safety and efficacy studies were brought in too.

I believe the Innovative Medicines Initiative work on combating antibiotic resistance is an excellent example of just how successful such international collaboration can be.