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Aiding Antibiotic Development with Deep Analysis of Resistance Evolution

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Genomic technique revolutionises drug development by identifying antibiotic resistance within a day

With random, little tweaks on the genetic makeup, scientists can now rapidly spot signs of resistance in bacteria – evidence that certain pathogens could soon demolish the defence wall of antibiotics.

Health

Just like all organisms, bacteria constantly strive to survive and thrive in an ever-changing world, facing shifting temperatures, varying food supplies and – horror of horrors – antibiotics. Mutations, changes in the DNA code, are the key drivers of evolution: even the smallest ones, a change of a single nucleotide, matter.

The antibiotics resistance crisis

Once deemed defenceless against the antibiotics developed 50 years ago, bacteria have altered their genetic machinery over time, shaking our confidence in antibiotics’ ability to control infectious diseases and save human lives. The outspoken warning issued on a groundbreaking UN report on drug resistance states that a growing number of common diseases are becoming untreatable. If no action is taken, the number of people worldwide that could die of infections that have grown resistant to drugs could reach 10 million per year by 2050. For billions of years, bacteria have been constantly evolving to become better suited to their environment. It is no surprise that they can now evolve resistance to antibiotics: “Unlike their no-resistance counterparts, resistant bacteria have a better chance of retaining their virulence and multiply even when exposed to antibiotics,” notes Csaba Pal, coordinator of the EU-funded Aware project. “Despite this global antibiotics resistance crisis, big pharmas are withdrawing their antibiotics research programmes, and this sounds frightening,” adds Pal. The researcher brings up the example of big pharmas that lost millions in examining antibiotic candidates that were impaired by resistance at a very late clinical phase.

Screening evolutionary changes on shorter timescales

Given this growing investment risk, the researcher and his team developed a pioneering method to rapidly test new antibiotic candidates for their potential to evolve resistance at a very early stage of clinical development. “Our genome engineering method, DIvERGE, puts a whole library of molecules under test, revealing probable resistance within a few days. Standing for ‘directed evolution with random genomic mutations’, our method allows a million-fold increase in the mutation rate along specific regions of the bacterial genome,” outlines Pal. “We usually introduce mutations to five loci in the bacteria genome that we deem likely to develop resistance. It only takes one or two days to generate billions of mutation combinations in the test tube.”

Proof-of-concept experiments

The ability to boost mutagenesis in bacteria in a very specific and controlled way could be a powerful strategy to guide drug development. But Pal then wondered: ”Is this just an airy-fairy game, or our method could indeed prove useful?” As proof of their concept, Pal and his team turned to gepotidacin, a potential first-in-class antibiotic currently in phase III clinical trials. Within two days, DIvERGE revealed that two specific mutations rendered the antibiotic completely ineffective. “To make matters worse, one of these mutations is found in many pathogenic bacteria out there, meaning that many of them are just one mutation or step away from developing resistance to gepotidacin,” notes Pal. In their quest to commercialise the technology, the researchers formed a non-exclusive licence agreement with an Israel-based company active in phage therapies. The team wishes to highlight the potential of DIvERGE to screen the resistance profiles of these viruses, which are deemed promising alternatives to antibiotics to eradicate pathogenic bacteria. The fear of the rapid emergence of resistance is a large obstacle to new drug development. “By revealing potential resistance mechanisms pretty early in the drug design process, our dream is to help pharmas prioritise the best compound candidates and hold them back from investing billions to bring new drugs whose efficacy could soon greatly diminish,” concludes Pal.

Keywords

Aware, resistance, bacteria, antibiotics, mutation, pharmas, genome, DIvERGE, directed evolution

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