Beating antibiotic resistance

New research into ‘resistance breaker’ drugs could help current antibiotics to combat antibiotic resistant infections more effectively...

Antimicrobials - medicines such as antivirals, antifungals, and antibiotics - are drugs that are used to treat infections in animals, plants, and humans. But, over time, microbes can develop resistances to these drugs, meaning some crucial medicines become ineffective. This resistance to antimicrobials is a growing problem: a recent study estimated that, in 2019, there were 4.95 million deaths globally associated with bacterial antimicrobial resistance. 

If we look back to the origins of antibiotics, the story begins with a battleground, but perhaps not one you’d expect. Bacteria and other microbes are at constant war with one another in the fight for resources. It’s in this environment that antibiotics first emerged, not by human scientific endeavour, but by evolution: survival of the fittest. Infectious disease specialist John Tregoning explains: “Antibiotics are mostly natural compounds that one bacterium makes to kill another, or one yeast makes to kill bacteria. [...] On any surface, the bacteria are fighting each other for the limited resources. So one strategy is to kill the other bacteria in the site, so you win that space.”

In this battle, one defense is for bacteria to evolve to be resistant to antibiotics. When use of antibiotics became more widespread, especially in healthcare and the agricultural industry, the environment that the bacteria were exposed to changed, applying a selective pressure that favoured certain strains endowed with antibiotic resistance genes. It’s this selective pressure that has accelerated antibiotic resistance.

Strains of bacteria with a lot of genes that give resistance to particular antibiotics are known as multidrug-resistant (MDR) or extensively drug-resistant (XDR). It’s difficult to treat MDR and XDR infections in humans, because there are only a limited number of options, and often, these options are so-called ‘last resort’ drugs. The more we use these agents, the higher the risk that bacteria will evolve resistance to them. According to Tregoning, it’s not a matter of if, but when. “If you look at the time course of when antibiotics were discovered and developed into a human clinical product, the resistance essentially emerged at almost exactly the same time. You can look at all of the different antibiotics, and the gap between antibiotic development and resistance emerging is often less than 5 years.”

How do we compete against bacteria when they evolve so quickly? Tregoning opines that there are a few approaches beyond just using less antibiotics. One option is to develop new drugs, but this is expensive and takes a long time. "It gets quite complicated in terms of how we fund and develop these drugs that ideally we never use.” In fact, the NHS are currently trialling a ‘subscription style’ payment plan to incentivise drug companies to develop new antibiotics, meaning the return on investment is not reflective of the amount of times the drug is used.

Another is vaccines. “We know that vaccines can protect against bacterial infections, and when you use a vaccine against a specific bacteria, you can see levels of antibiotic resistance in that bacteria dropping as well, because people aren’t getting as sick, so they don’t need as much treatment.”

The final option is to develop resistance breaking drugs: these are compounds that will make current antibiotics more effective against bacteria that have resistance genes for that antibiotic. Take penicillin for example; it’s one of a number of antibiotics called beta-lactams. Bacteria resistant to beta-lactam treatments have genes that produce enzymes called beta-lactamases. These enzymes, says Tregoning, are like “a very specific pair of scissors that can chop penicillin into small bits.” The next step in this drugs ‘arms race’ is to develop compounds that stop these enzymes from breaking apart the antibiotics, “that basically blunt the scissors that cut the penicillin up.”

Researchers at Oxford University have done just that. “Enzymes have an active cleft - the 'lock and key' is the most common model people use to describe it - but, basically, they have a space that binds the thing that they’re going to chew up. What this group at Oxford have done is produce a compound that sits in that site and stops it being able to chew up the [antibiotic].” It’s hoped that these enzyme-blocking drugs can restore the activity of beta-lactam antibiotics such as penicillin and, more importantly, also restore the activity of carbapenems, ‘last-resort’ beta-lactams that are used to treat MDR and XDR infections.