Bill Broadhurst – The Answer Lies in the Soil

Writing this article in the middle of the COVID-19 crisis, it might seem churlish to ask readers to focus their attention on another impending healthcare apocalypse. However, my academic research has applications in one such area:  the growing worldwide problem of antibiotic-resistant bacteria.

Bacteria are the secret masters of our planet. They predate multicellular eukaryotes such as ourselves by two billion years, and are more numerous and diverse. Bacteria are master innovators because they reproduce rapidly and mutate frequently; when they learned how to convert sunlight into energy for growth by splitting water, the waste product, oxygen, transformed forever Earth’s atmosphere, oceans and geology.

The discovery of antibiotic drugs that could keep bacterial pathogens in check had a similarly dramatic effect on human life expectancy in the second half of the twentieth century. Today, the prospect of returning to an antibiotic-free world in which routine operations result in life-threatening infections seems unbearable. Caesarean sections and hip replacements could become too risky to attempt. Treatments that rely on antibiotics to offset suppression of the immune system, such as cancer chemotherapy or organ transplants, could also be lost. In addition, multi-drug-resistant infectious diseases, from tuberculosis to gonorrhoea, are already challenging healthcare providers.

Market forces are not able to resolve this problem. Since the golden age of antibiotic discovery, 1940-60, pharmaceutical companies have gradually withdrawn investment from the field. Bacteria acquire resistance so rapidly that the therapeutic window for a widely used new antibiotic to be effective and a company to recoup its investment is less than a year. What clinicians need most is a novel drug that will hardly be used at all, to hold in reserve for otherwise intractable infections.

The key to understanding and tackling antibiotic resistance lies in remembering where these drugs come from. More than two-thirds of the antibiotics in clinical use are derived from natural products, the most abundant source being soil bacteria. Thousands of biologically active molecules have been isolated from these microbes, including antibacterial, antifungal, anticancer and immunosuppressant agents. Apart from a suspicion that they must confer a competitive advantage over their neighbours, we have little idea why soil bacteria go to the trouble of synthesising such complex molecules.

Bacteria that produce antibiotics must evolve a mechanism of genetically encoded resistance to avoid committing suicide. This could involve a decoy version of a drug’s target, so the antibiotic will not incapacitate the producer cell, or overproducing efflux pumps to flush away dangerous molecules as soon as they are made. Innovations of this sort are spread by cells of the same species sharing fragments of their DNA, but this genetic information can also be taken up by different types of microbe, opening a route for antibiotic resistance to spread from producer strains to pathogens. Soil bacteria have been making antibiotics for billions of years, so DNA fragments that encode protective genes are ubiquitous in the environment. This is why resistance to a newly developed antibacterial agent will inevitably occur.

Thankfully, the advent of cheap and rapid technologies for reading bacterial genome sequences has opened up new fronts in the arms race against multi-drug-resistant pathogens. One crucial discovery was that the blueprints required for assembling each natural product tend to group together, creating ‘biosynthetic gene clusters’. A second finding was that, based on the number of known bioactive molecules, the genomes of well-known producer strains contain more clusters than expected. If we work out how to activate them, these ‘silent’ biosynthetic gene clusters could yield new drug candidates. Thirdly, it is possible to sequence the genomes of bugs that do not thrive in laboratories and so have remained uncharacterised, such as marine bacteria, revealing novel gene clusters that make antibiotic agents that have not previously been used above sea level. Finally, synthetic biology permits us to tinker with existing gene clusters, persuading them to produce ‘unnatural’ natural products that access previously unexplored regions of chemical space.

Following this last option, my research group has performed precision surgery on genes that encode polyketide synthases, a class of biosynthetic factory enzymes that produce the respiratory system antibiotic erythromycin and other commercial drugs. We succeeded in broadening the chemical variety of extender molecules that can be stitched together by the synthase, which could breathe new life into old drugs. We are using the tools of structural biology to reveal how polyketide synthases really work. We have uncovered rules that explain how one small component acts like a conveyor belt to shuttle substrate molecules around the factory, swinging on molecular bungee cords to make brief contacts with multiple enzymatic active sites. My hope is that as we learn more, it will become possible to reprogram natural polyketide synthases to produce huge quantities of new compounds that can then feed into  drug discovery trials.