Comparative genomics of Alexander Fleming's celebrated fungus Penicillium rubens (IMI 15378) sheds light on the evolution of penicillin synthesis genes

Antibiotics are derived from wild organisms and understanding how they evolve among different lineages might help with the discovery and optimisation of new antibiotics. We report the draft genome sequence of Alexander Fleming's original fungus behind the discovery of penicillin and modern use of antibiotics, now classified as Penicillium rubens (IMI 15378). We compare the structure of the genome and the sequences of a suite of genes involved in penicillin synthesis with those in two closely related 'high producing' domesticated strains of P. rubens and another penicillin-producing member of Penicillium section Chrysogena, P. nalviogense. The main effector genes (pcbAB, pcbC and penDE) and the regulatory gene cefD2 show amino acid divergence between the Fleming strain and both Wisconsin strains, whereas other regulatory genes are conserved. Partial duplication of fragments of penicillin-pathway genes has occurred in all three strains, to differing degrees, which we hypothesise might be involved in the regulation of the pathway. The two Wisconsin strains are identical in gene sequences and only vary in duplication of the pcbAB-pcbC-penDE complex and partial duplication of fragments of regulatory genes. We conclude that long-term evolution in the wild encompasses both sequence changes of the effector genes and gene duplication, whereas human-mediated changes through mutagenesis and artificial selection acted solely on duplication of the penicillin pathway genes.