Combining expertise to produce novel combination drugs
Antibiotics are a vital foundation of modern medicine, however common infections and injuries that were once easily treatable are becoming more dangerous.
This is because like all living things, bacteria have changed over time to adapt to their surroundings. Antibiotic resistance occurs when bacteria evolve in a way that makes antibiotic drugs ineffective to treat the infections that they cause. It is estimated that over 1.2 million people died from drug-resistant infections in 2019.
Bacteria can survive antibiotic treatment in several ways. Some bacteria can neutralise the antibiotic before it can work. Others have evolved to quickly pump the antibiotic out of their cells. And others can change their outer structure so the antibiotic cannot attach to the bacteria and kill them.
New antibiotics are urgently needed to fight the epidemic of antibiotic resistance.
Dr Monisha Singha is a synthetic chemist at the IOI working on antibiotic combination treatments. An antibiotic combination treatment includes an antibiotic and an inhibitor. The inhibitor prevents specific bacterial enzymes from breaking down the antibiotic before it has its desired effect to treat the infection.
Metallo- β -lactamases are bacterial enzymes that breakdown β-lactam antibiotics like carbapenems, which are used to treat serious multidrug-resistant infections when other antibiotics such as penicillin have failed. There are currently no clinically approved Metallo-β-lactamases inhibitors – this what the IOI team are working on.
The first step is to design an inhibitor compound. “It’s important from the very first step before we get into the lab to consider the drug’s intended purpose for the patient. There is no point synthesising a new drug which works in theory but will be toxic to the patient. We work closely with the IOI team in biology to use their expertise on how molecules might interact inside a cell and inside the human body to inform drug design.”
Since 2017 only 12 new antibiotics have been approved, of which 10 belong to classes with known resistance mechanisms that hinder their effectiveness at treating infections. IOI collaborates closely with industry to ensure that research in our labs can be translated into action against the growing global health threat of antibiotic resistance.
“If there are too many steps in the synthetic process, if the starting materials are expensive or not easily available, then this increases cost of production and decreases likelihood of pharmaceutical companies investing in getting a drug to market. Finding new drugs is hard; finding new drugs that meet all our requirements that are also appealing to pharma is very hard.”
When the team have several new antibiotic compounds to test, scientists at the IOI biology lab screen the molecules against resistant bacteria. Based on this biological data the team decide next steps: whether modifications are needed in the chemical structure of the potential drug molecules to make the drug more potent (known as lead optimization), or they are good to go for the next stages in the drug development pipeline.
Clear routes for collaboration to enhance drug development are integral to the IOI as an interdisciplinary institute.
It is so exciting to be creative with molecule design at this stage of the drug development process. I always find it very rewarding to make a molecule that may never have been synthesised before, and working so closely with biologists is crucial to our success.”
Learn more about IOI work on human antibiotics here: https://www.ineosoxford.ox.ac.uk/research/areas-of-focus/antibiotics