Abstract
Antibiotics were derived originally from wild organisms and therefore understanding how these compounds evolve among different lineages might help with the design of new antimicrobial drugs. We report the draft genome sequence of Alexander Fleming’s original fungal isolate behind the discovery of penicillin, now classified as Penicillium rubens Biourge (1923) (IMI 15378). 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 main effector genes for producing penicillin G (pcbAB, pcbC and penDE) show amino acid divergence between the Fleming strain and both industrial strains, whereas a suite of regulatory genes are conserved. Homologs of penicillin N effector genes cefD1 and cefD2 were also found and the latter displayed amino acid divergence between the Fleming strain and industrial strains. The draft assemblies contain several partial duplications of penicillin-pathway genes in all three P. rubens strains, to differing degrees, which we hypothesise might be involved in regulation of the pathway. 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. 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.
Highlights
Clinical use of antibiotics has revolutionised treatment of bacterial infection
Gene duplication might lead to increased expression of the enzyme if the copies are conserved, or to production of multiple variants of the antibiotic if paralogous copies diverge in function[13]
We compare Fleming’s isolate to two industrial strains of P. rubens derived from a second isolation from the wild in the USA. These strains were originally misnamed as P. chrysogenum but were subsequently shown by multigene analysis to belong to the P. rubens clade[3,4]
Summary
Clinical use of antibiotics has revolutionised treatment of bacterial infection. The characterization of p enicillin[1] followed from Alexander Fleming’s discovery of lysis and inhibition of the growth of Staphylococcus on petri dishes colonized by the fungus Penicillium rubens[2] (named at the time as P. notatum, and until recently as P. chrysogenum[3,4]). 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). Differences between the two industrial strains are solely the result of mutagenesis and artificial selection for high production: for example, comparison of P2niaD18 to the original Wisconsin 54-1255 g enome[17] revealed evidence for structural rearrangements and tandem duplication of penicillin-producing genes caused by the mutagenesis[20]. The third gene penDE encodes the enzyme isopenicillin N acyltransferase, which catalyses the final step of the biosynthetic pathway that synthesizes penicillin G 27,29 This gene is hypothesized to have evolved within the beta-lactam producing fungi rather than being horizontally acquired from b acteria[24].
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