Mold regrown from Fleming's frozen sample [CABI]

Researchers from Imperial College London, CABI, and the University of Oxford, have sequenced the genome of Alexander Fleming’s penicillin mold for the first time, and compared it to strains that are used for industrial penicillin manufacture today. The results indicate that the Fleming strain and the U.S. strain use slightly different mechanisms to produce penicillin, which could point to new routes for industrial production.

Research lead Timothy Barraclough, PhD, from the Department of Life Sciences at Imperial and the Department of Zoology at Oxford, said: “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.” Ayush Pathak, PhD, at the Department of Life Sciences at Imperial, added, “Our research could help inspire novel solutions to combating antibiotic resistance.” Pathak is first author of the team’s published paper in Scientific Reports, which is titled, “Comparative genomics of Alexander Fleming’s original Penicillium isolate (IMI 15378) reveals sequence divergence of penicillin synthesis genes.”

Alexander Fleming famously discovered the first antibiotic, penicillin, in 1928, while working at St Mary’s Hospital Medical School, which is now part of Imperial College London. The antibiotic was produced by a mold of the genus Penicillium, which accidentally started growing in a Petri dish. The isolate is now classified as Penicillium rubens Biourge (1923) (IMI 15378).

Fleming’s sample [CABI]

In their published paper, the researchers describe how they set out to sequence the genome of Fleming’s original Penicillium strain, by reviving the fungus from a sample that had been frozen alive, more than 50 years ago, which was housed as part of the culture collection at CABI.

“In order to gain insights into the evolution of genes underlying the production of the classic antibiotic, penicillin, we here present a draft genome sequence for Fleming’s original isolate, Penicillium rubens (IMI 15378),” they explained. “Cryopreserved living samples of this isolate are kept in numerous global collections, and we revived the fungus from the CABI (IMI) living culture collection for DNA extraction and whole-genome sequencing.”

Although Fleming’s mold is famous as the original source of penicillin, industrial production quickly moved to using fungus from moldy cantaloupes in the U.S. From these natural beginnings, the Penicillium samples were artificially selected for strains that produce higher volumes of penicillin. The team used the new genome information from the Fleming mold sequence to compare the original strain with two strains of Penicillium from the U.S. that are used to produce the antibiotic on an industrial scale. “We compare the structure of the genome and genes involved in penicillin synthesis with those in two ‘high producing’ industrial strains of P. rubens and the closely related species P. nalgiovense,” the team noted.

The researchers were particularly interested in two kinds of genes, those encoding the enzymes that the fungus uses to produce penicillin, and those that regulate the enzymes, for example by controlling how many enzymes are made. They found that in both the UK and U.S. strains, the regulatory genes had the same genetic code, but the U.S. strains had more copies of the regulatory genes, helping those strains produce more penicillin.

However, the genes coding for penicillin-producing enzymes differed between the strains isolated in the U.K. and U.S. The researchers say this shows that wild Penicillium in the U.K. and U.S. evolved naturally to produce slightly different versions of these enzymes. “The two industrial strains are identical in sequence across all effector and regulatory genes but differ in duplication of the pcbAB–pcbC–penDE complex and partial duplication of fragments of regulatory genes,” the investigators commented. “We conclude that evolution in the wild encompassed both sequence changes of the effector genes and gene duplication, whereas human-mediated changes through mutagenesis and artificial selection led to duplication of the penicillin pathway genes.”

Fleming’s sample in a tube [CABI]

Molds like Penicillium produce antibiotics to fight off microbes, and are in a constant arms race as microbes evolve ways to evade these defenses. The U.K. and U.S. strains likely evolved differently to adapt to their local microbes. Microbial evolution is a big problem today, as many are becoming resistant to our antibiotics. Although the researchers say they don’t yet know the consequences of the different enzyme sequences in the U.K. and U.S. strains for the eventual antibiotic, they say it does raise the intriguing prospect of new ways to modify penicillin production.

First author Ayush Pathak, from the Department of Life Sciences at Imperial, said, “Industrial production of penicillin concentrated on the amount produced, and the steps used to artificially improve production led to changes in numbers of genes. 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.”

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