Drug resistant infections are responsible for hundreds of thousands of deaths every year and this global problem is only getting worse. As bacteria evolve resistance to the limited number of antibiotics currently available, we urgently need to develop new more effective treatments against a huge number of different infectious bacteria and pathogens.
Crick Group Leader, Eachan Johnson, is in the business of understanding what makes a good antibiotic and also how to make them. We spoke to him about an ambitious project starting in his lab, with support granted by the European Research Council.
We have entered a post-antibiotic era, where we have identified for each known antibiotic at least one strain of bacteria which is resistant. Researchers are desperate to find new treatment options for a range of infections but this is becoming more and more difficult as the low-hanging fruit has been exhausted, whereas bacteria continue to be are very good at enduring treatment and evolving resistance to antibiotics.
For example, one bacterium my lab studies is M. tuberculosis, which causes TB. This infection already kills more than a million people every year and is poised to become an even greater threat, as some M. tuberculosis bacteria have evolved to become drug resistant to every licensed drug. These bacteria spread, increasing the prevalence of drug-resistant TB.
The cycle of slowly discovering new antibiotics and then pathogens becoming resistant to them is unsustainable and a very real threat to human health. To regain the initiative, society needs to both increase the rate of discovery and decrease the rate of resistance by grounding new therapies in a detailed understanding of how bacteria evolve. This way, we could stay one step ahead of antibiotic resistance.
There are some important gaps in our knowledge of bacterial adaptation.
Firstly, how do bacteria rapidly accumulate mutations that enable drug resistance? We want to identify specific mechanisms that are essential for bacteria to evolve and become drug resistant. With this understanding, we might be able to design new drugs that interfere with the evolution of drug resistance.
And how do small populations of pathogens survive treatment and then re-emerge? Understanding the different defence strategies that bacteria employ against antibiotics will help us design better drugs that are harder to become tolerant to.
Finally, what chemical rules allow drugs to reach target pathogens and how are they entering the bacterial cell? This level of molecular detail has been hugely valuable in developing cancer treatments that reach their target tumour cells and effectively kill them. But the antibiotic research field is fragmented because of the huge number of different bacteria--both established and emerging--we’re tackling. Each one will respond differently to treatments because they reside in diverse niches and have cell walls that have distinct structures.
Our study is broken in two complementary approaches – the biological research of identifying the mechanisms by which bacteria evolve resistance and survive antibiotic stress, and chemical screening for potential new drug compounds which interfere with those same mechanisms.
We’ll be identifying the genes involved in drug resistance in different bacterial species. How bacteria pick up mutations in response to stress, how they adopt a drug tolerant state, and how they exit this state to re-establish infection. These tolerant states have historically been difficult to study because the bacteria grow very slowly, if at all. So we’re developing new methods which will allow us to manipulate and probe the secret life of drug tolerant bacteria.
We’ll also be screening huge libraries of different compounds against thousands of genetic knockouts of several species of pathogenic bacteria. This will help us understand which compounds get into the cell and why, and tell us exactly how each compound is affecting each bacterium. It’s a high-resolution view of how drugs might target bacterial cells.
Importantly, we’re looking at all this directly in the same pathogens, like M. tuberculosis, that infect people. Many studies into antibiotic resistance and tolerance rely on easy-to-use domesticated bacteria which have lost the ability to infect, but we want to develop an in-depth biological understanding that’s as close as possible to clinical strains of bacteria.
We hope that a better appreciation of bacterial physiology, combined with a platform to pick out compounds most likely to be effective against specific pathogens, will help secure the future of treatments for infections, allowing researchers to rapidly discover and develop new drugs.
Our project in a nutshell is finding the general principles of how to discover new, effective antibiotics. We want to create methods that could be rapidly deployed in response to emerging antibiotic resistance.
If scientists can apply this knowledge, and create new drugs that target the pathogen’s ability to evolve, we will not only have a more sustainable solution to antibiotic resistance, but will also have more effective drugs that work for more people. I would like to see more people survive infections like TB in the future.
Eachan has been awarded an ERC starting grant funded by UKRI.
