Alexander Fleming is famous for discovering the very first antibiotic in 1928. It was penicillin, grown accidently in a petri dish. Its curative powers are legendary. Back then researchers were quick to reproduce the life-saving medicine at scale. That required a few adaptations in manufacturing plans in order to ramp up production on a global scale. It wasn’t until the year 2020 that differences in how penicillin is produced provided an important clue on new ways to defeat resistant microbes.
How penicillin strains came to be
Fleming’s original penicillin discovery came from a Penicillium mold that found its own way into his petri dish from the atmosphere. It promptly killed the infectious bacteria culture Fleming was growing in that dish. And the rest, as they say, is history. Or the rest is a video if you don’t recall the recounting of historic events…
As is typical of such discoveries, the initial amount produced is only sufficient to test and prove the theory behind a potential treatment or cure. In order to eventually treat patients, larger batches must then be produced to use in animal and/or human safety and efficacy tests. Providing all is successful in the testing phases, then the drug must be produced on a massive scale to treat millions of patients over many years in many countries.
Each of those many different countries produce the same medicine – in this case penicillin – but in slightly different ways. There are also differences in drug production between factories in the same county. This leads to versions, or strains, of penicillin.
What the difference between drug strains revealed
Researchers only recently sequenced the genome of Fleming’s original Penicillium strain. They extracted DMA from samples that were frozen over 50 years ago.
“We originally set out to use Alexander Fleming’s fungus for some different experiments, but we realized, to our surprise, that no-one had sequenced the genome of this original Penicillium, despite its historical significance to the field,” said Lead researcher Professor Timothy Barraclough, from the Department of Life Sciences at Imperial and the Department of Zoology at Oxford in a statement to the press.
Researchers from Imperial College London, CABI and the University of Oxford then compared the genome of the original strain to later, industrialized strains which came from a variety of sources such as fungus from moldy cantaloupes. You can find the full scientific report in Nature. But here is the upshot:
“In both the UK and US strains, the regulatory genes had the same genetic code, but the US strains had more copies of the regulatory genes, helping those strains produce more penicillin,” said the researchers.
“However, the genes coding for penicillin-producing enzymes differed between the strains isolated in the UK and US. The researchers say this shows that wild Penicillium in the UK and US evolved naturally to produce slightly different versions of these enzymes. The UK and US strains likely evolved differently to adapt to their local microbes.”
The researchers don’t yet know “the consequences of the different enzyme sequences in the UK and US strains for the eventual antibiotic,” but they did conclude that “it does raise the intriguing prospect of new ways to modify penicillin production.”
The ability to purposefully modify penicillin and other antibiotics to deliberately counter specific antibiotic-defenses in microbes would be a huge win in the war against ever-evolving disease threats.
“Our research could help inspire novel solutions to combatting antibiotic resistance. Industrial production of penicillin concentrated on the amount produced, and the steps used to artificially improve production led to changes in numbers of genes,” said first author Ayush Pathak, from the Department of Life Sciences at Imperial.
“But it is possible that industrial methods might have missed some solutions for optimizing penicillin design, and we can learn from natural responses to the evolution of antibiotic resistance.”
Bioinformatics will help us learn and then weaponize what we learn about destroying the changing defenses of many infectious microbes. Optimizing drug production is likely just the beginning salvo.