Penicillium rubens

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Penicillium rubens
Penicillium rubens (type specimen).png
Scientific classification OOjs UI icon edit-ltr.svg
Kingdom: Fungi
Division: Ascomycota
Class: Eurotiomycetes
Order: Eurotiales
Family: Aspergillaceae
Genus: Penicillium
Species:
P. rubens
Binomial name
Penicillium rubens
Biourge (1910)

Penicillium rubens is a species of fungus in the genus Penicillium and was the first species known to produce the antibiotic penicillin. It was first described by Philibert Melchior Joseph Ehi Biourge in 1923. In 1929, Alexander Fleming at St Mary's Hospital, London discovered that the fungus produced an antibiotic that killed bacteria, and named the unknown compound penicillin. For the discovery and development of penicillin, Fleming shared the 1945 Nobel Prize in Physiology or Medicine with Ernst Boris Chain and Howard Florey. [1]

Contents

There was long history of controversy on the exact identification of the original penicillin-producing species and was variously identified as Penicillium rubrum , P. notatum, and P. chrysogenum among others. It was only after genomic comparison and phylogenetic analysis in 2011 that the species was resolved as P. rubens. [2] [3] P. rubens is the best source of penicillins such as benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K). It also produces another class of antibiotics, cephalosporins. It is also the source of other important bioactive compounds such as andrastin, chrysogine, fungisporin, roquefortine, and sorbicillins. [4] [5]

History

Belgian microbiologist Philibert Melchior Joseph Ehi Biourge was the first to describe P. rubens in 1923. [6] The medicinal importance was discovered by Alexander Fleming, a physician at St Mary's Hospital, London. In September 1928, Fleming found that one of his bacterial cultures (of Staphylococcus aureus ) was contaminated with mould, and that the area around the mould inhibited bacterial growth. He gave the name penicillin for the purported antibacterial substance produced by the mould. After a series of experimental tests, he published his discovery in the June 1929 issue of the British Journal of Experimental Pathology. [7] With the help of his colleague Charles J. La Touche, Fleming identified the fungus as Penicillium rubrum. [1]

But Charles Thom at the U. S. Department of Agriculture, Peoria, Illinois, compared the specimen with his collection of Penicillium species, and corrected the species as P. notatum. In his publication in 1931, he resolved that P. notatum was a member of P. chrysogenum species complex, which he had described in 1910. [8] P. notatum was described by Swedish chemist Richard Westling in 1811. Thom adopted and popularised the use of P. chrysogenum. [9] After discovery of other new species and taxonomic reexamination, three species, P. notatum, P. meleagrinum, and P. cyaneofulvum were recognised as P. chrysogenum. [10] [11] The Seventeenth International Botanical Congress held in Vienna, Austria, in 2005 adopted the name P. chrysogenum as the conserved name ( nomen conservandum). [12]

Whole genome sequence and phylogenetic analysis, particularly using β-tubulin sequences, in 2011 showed that P. notatum is P. rubens, and that P. chrysogenum is a different species. [2] [13]

Biology

Penicillium rubens (CBS 205.57 = NRRL 824 = IBT 30142), Fleming's original penicillin-producer. A-C. Colonies seven-day-old 25degC. A. Colonies in Czapek yeast extract agar. B. Colonies in malt extract agar. C. Colonies in yeast extract sucrose agar. D-H. Conidiophores. I. Conidia. Bars = 10 mm. Penicillium rubens (Fleming's strain).png
Penicillium rubens (CBS 205.57 = NRRL 824 = IBT 30142), Fleming's original penicillin-producer. A–C. Colonies seven-day-old 25°C. A. Colonies in Czapek yeast extract agar. B. Colonies in malt extract agar. C. Colonies in yeast extract sucrose agar. D–H. Conidiophores. I. Conidia. Bars = 10 μm.

P. rubens is a common fungus of indoor environment. Along with Cladosporium halotolerans and Aspergillus niger, it is one of the nuisance moulds when humidity is high. It is the most resilient mould as it needs less water for growth and propagation. [14] It has a soft and velvety surface. The spore-bearing filaments, conidiophores are smooth and measure 200-300 μm in length. The hairy surface, penicilli are 8-12 μm long. The conidia are smooth-walled, ellipsoidal in shape, measuring 2.5-4.0 μm long, and are blue or bluish-green in colour. [15] It exists in a number of strains, of which the most important are Fleming's strain (designated CBS 205.57 or NRRL 824 or IBT 30142) from which the first penicillin was discovered and the Wisconsin strain (NRRL1951) obtained from a cantaloupe in Peoria, Illinois, in 1944 and has been used for industrial production of penicillin G. [16] The original Wisconsin strain itself has been produced in a variety of strains. [17]

Genome

P. rubens has four chromosomes. [18] The genome of the Wisconsin strain has been most studied. The nuclear genome of 54-1255 strain, regarded as low-penicillin producer, has a size of 32.19 Mb. There are 13,653 open reading frames (ORFs), including 592 probable pseudogenes and 116 truncated ORFs. [19] Three genes, namely pcbAB, pcbC, and penDE constitute the core sites for penicillin biosynthesis. They are distributed in clusters among other (ORFs) in a 58.8 kb region, [20] on chromosome 2. [18] [17] pcbAB encodes an enzyme α-aminoadipoyl-L-cysteinyl-D-valine synthetase, pcbC encodes isopenicillinN (IPN) synthase, and penDE, encoding acyl-CoA:isopenicillinN acyltransferase. [21] The high penicillin-producing strain, NCPC10086, has slightly larger genome of 32.3 Mb, with about 13,290 protein-coding genes. There are at least 69 genes not present in 54-1255 strain. The gene Pch018g00010 that codes for enzymes in glutathione metabolism is considered as the key factor in enhanced penicillin production of this strain. [22]

The mitochondrial genome consists of 31,790 bp and 17 ORFs. [19] Enzymes of the final biosynthetic pathway such as acyl-CoA:isopenicillinN acyltransferase28 and phenylacetyl-CoA ligase are trafficked to separate cell organelles called microbodies (peroxisomes). The peroxisome gene pex11 is essential for controlling the amount of penicillin synthesis; the more the gene is activated (expressed), the more the penicillins. [23]

Uses

P. rubens is the source of β-lactam antibiotics, principally of penicillins and to a lesser extent, cephalosporins. [24] The species produces three penicillins, benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K). [25] Penicillin G is a naturally occurring compound that was first isolated and used as an antibiotic. [26] [27] [28] Penicillins from P. rubens are effective against Gram-positive bacteria such as the species of Bacillus , Clostridium , Corynebacterium, Pneumococcus, Streptococcus , and Staphylococcus. [29] They are clinically used to treat actinomycosis, anthrax, botulism, clostridial infections, diphtheria, empyema, endocarditis, food poisoning (due to Listeria ), gas gangrene, meningitis, pneumonia, pericarditis, septicaemia, and syphilis. [30] However, they are useless against Gram-negative bacteria since these bacteria are impermeable to the compounds because of their additional outer cell membrane, as well as some species producing pencillases (β-lactamases) that destroy the penicillin structure (β-lactam ring). [31] However, semisynthetic penicillins like aminopenicillins (ampicillin, amoxicillin, and bacampicillin), carboxypenicillins (carbenicillin and ticarcillin) and ureidopenicillins (mezlocillin, azlocillin, and piperacillin) have been developed that are effective against these bacteria. [32]

Cephalosporins, naturally produced by other fungi belonging to the genus Acremonium , are one of the most widely used antibiotics by clinicians and is also produced by P. rubens. [33] However, they are not naturally produced by P. rubens. Cephalosporins are synthesised from the same biochemical pathway as penicillin biosynthesis, but requires two additional enzymes (such as deacetoxycephalosporin C synthase/hydroxylase and deacetylcephalosporin C acetyltransferase) which are absent in P. rubens. [34] [35] However, P. rubens is genetically engineered to produce the antibiotics by activating the specific genes (cefEF and cefG) that led to the production of the essential enzymes. [36] [37]

References

  1. 1 2 Lalchhandama, K. (2020). "Reappraising Fleming's snot and mould". Science Vision. 20 (1): 29–42. doi: 10.33493/scivis.20.01.03 .
  2. 1 2 Houbraken, Jos; Frisvad, Jens C.; Samson, Robert A. (2011). "Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens". IMA Fungus. 2 (1): 87–95. doi:10.5598/imafungus.2011.02.01.12. PMC   3317369 . PMID   22679592.
  3. ↑ Hibbett, David S.; Taylor, John W. (2013). "Fungal systematics: is a new age of enlightenment at hand?" . Nature Reviews Microbiology. 11 (2): 129–133. doi:10.1038/nrmicro2963. PMID   23288349. S2CID   17070407.
  4. ↑ Visagie, C.M.; Houbraken, J.; Frisvad, J.C.; Hong, S.-B.; Klaassen, C.H.W.; Perrone, G.; Seifert, K.A.; Varga, J.; Yaguchi, T.; Samson, R.A. (2014). "Identification and nomenclature of the genus Penicillium". Studies in Mycology. 78: 343–371. doi:10.1016/j.simyco.2014.09.001. PMC   4261876 . PMID   25505353.
  5. ↑ Pohl, Carsten; Polli, Fabiola; Schütze, Tabea; Viggiano, Annarita; Mózsik, László; Jung, Sascha; de Vries, Maaike; Bovenberg, Roel A. L.; Meyer, Vera; Driessen, Arnold J. M. (2020). "A Penicillium rubens platform strain for secondary metabolite production". Scientific Reports. 10 (1): 7630. Bibcode:2020NatSR..10.7630P. doi:10.1038/s41598-020-64893-6. PMC   203126 . PMID   32376967.
  6. ↑ Biourge, P. (1923). "Les moissisures du groupe Penicillium Link". La Cellule. 33: 7–331.
  7. ↑ Fleming, Alexander (1929). "On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their Use in the Isolation of B. influenzæ". British Journal of Experimental Pathology. 10 (3): 226–236. doi:10.1093/clinids/2.1.129. JSTOR   4452419. PMC   2048009 . PMID   11545337.
  8. ↑ "Appendix. History of species used and Dr. Thom's diagnoses of species". Philosophical Transactions of the Royal Society of London. Series B, Containing Papers of a Biological Character. 220 (468–473): 83–92. 1931. doi: 10.1098/rstb.1931.0015 .
  9. ↑ Thom, Charles (1945). "Mycology Presents Penicillin". Mycologia. 37 (4): 460–475. doi:10.2307/3754632. JSTOR   3754632.
  10. ↑ Samson, R. A.; Hadlok, R.; Stolk, Amelia C. (1977). "A taxonomic study of the Penicillium chrysogenum series". Antonie van Leeuwenhoek. 43 (2): 169–175. doi:10.1007/BF00395671. PMID   413477. S2CID   41843432.
  11. ↑ Scott, James; Untereiner, Wendy A.; Wong, Bess; Straus, Neil A.; Malloch, David (2004). "Genotypic variation in Penicillium chysogenum from indoor environments". Mycologia. 96 (5): 1095–1105. doi:10.1080/15572536.2005.11832908. PMID   21148929. S2CID   30505910.
  12. ↑ "International Code of Botanical Nomenclature (VIENNA CODE). Appendix IV Nomina specifica conservanda et rejicienda. B. Fungi". International Association of Plant Taxonomy. 2006. Retrieved 17 June 2020.
  13. ↑ Houbraken, J.; Frisvad, J.C.; Seifert, K.A.; Overy, D.P.; Tuthill, D.M.; Valdez, J.G.; Samson, R.A. (2012-12-31). "New penicillin-producing Penicillium species and an overview of section Chrysogena". Persoonia - Molecular Phylogeny and Evolution of Fungi. 29 (1): 78–100. doi:10.3767/003158512X660571. PMC   3589797 . PMID   23606767.
  14. ↑ Segers, Frank J. J.; van Laarhoven, Karel A.; Huinink, Hendrik P.; Adan, Olaf C. G.; Wösten, Han A. B.; Dijksterhuis, Jan (2016). Brakhage, A. A. (ed.). "The Indoor Fungus Cladosporium halotolerans Survives Humidity Dynamics Markedly Better than Aspergillus niger and Penicillium rubens despite Less Growth at Lowered Steady-State Water Activity". Applied and Environmental Microbiology. 82 (17): 5089–5098. Bibcode:2016ApEnM..82.5089S. doi:10.1128/AEM.00510-16. PMC   4988216 . PMID   27316968.
  15. ↑ "Penicillium rubens Biourge ATCC ® 28089™". www.atcc.org. Retrieved 2020-06-17.
  16. ↑ Raper, K. B.; Alexander, D. F.; Coghill, R. D. (1944). "Penicillin: II. Natural Variation and Penicillin Production in Penicillium notatum and Allied Species". Journal of Bacteriology. 48 (6): 639–659. doi:10.1128/JB.48.6.639-659.1944. PMC   374019 . PMID   16560880.
  17. 1 2 Martín, Juan F. (2020). "Insight into the Genome of Diverse Penicillium chrysogenum Strains: Specific Genes, Cluster Duplications and DNA Fragment Translocations". International Journal of Molecular Sciences. 21 (11): 3936. doi: 10.3390/ijms21113936 . PMC   7312703 . PMID   32486280.
  18. 1 2 Fierro, Francisco; Gutiérrez, Santiago; Diez, Bruno; Martín, Juan F. (1993). "Resolution of four large chromosomes in penicillin-producing filamentous fungi: the penicillin gene cluster is located on chromosome II (9.6 Mb) in Penicillium notatum and chromosome 1 (10.4 Mb) in Penicillium chrysogenum". Molecular and General Genetics. 241–241 (5–6): 573–578. doi:10.1007/BF00279899. PMID   8264531. S2CID   13542522.
  19. 1 2 van den Berg, Marco A; Albang, Richard; Albermann, Kaj; Badger, Jonathan H; Daran, Jean-Marc; M Driessen, Arnold J; Garcia-Estrada, Carlos; Fedorova, Natalie D; Harris, Diana M; Heijne, Wilbert H M; Joardar, Vinita (2008). "Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum". Nature Biotechnology. 26 (10): 1161–1168. doi: 10.1038/nbt.1498 . PMID   18820685.
  20. ↑ Díez, B.; Gutiérrez, S.; Barredo, J. L.; van Solingen, P.; van der Voort, L. H.; Martín, J. F. (1990). "The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes". The Journal of Biological Chemistry. 265 (27): 16358–16365. doi: 10.1016/S0021-9258(17)46231-4 . PMID   2129535.
  21. ↑ Fierro, F.; Barredo, J. L.; Diez, B.; Gutierrez, S.; Fernandez, F. J.; Martin, J. F. (1995). "The penicillin gene cluster is amplified in tandem repeats linked by conserved hexanucleotide sequences". Proceedings of the National Academy of Sciences. 92 (13): 6200–6204. Bibcode:1995PNAS...92.6200F. doi: 10.1073/pnas.92.13.6200 . PMC   41670 . PMID   7597101.
  22. ↑ Wang, Fu-Qiang; Zhong, Jun; Zhao, Ying; Xiao, Jingfa; Liu, Jing; Dai, Meng; Zheng, Guizhen; Zhang, Li; Yu, Jun; Wu, Jiayan; Duan, Baoling (2014). "Genome sequencing of high-penicillin producing industrial strain of Penicillium chrysogenum". BMC Genomics. 15 (Suppl 1): S11. doi: 10.1186/1471-2164-15-S1-S11 . PMC   4046689 . PMID   24564352.
  23. ↑ Kiel, Jan A.K.W.; van der Klei, Ida J.; van den Berg, Marco A.; Bovenberg, Roel A.L.; Veenhuis, Marten (2005). "Overproduction of a single protein, Pc-Pex11p, results in 2-fold enhanced penicillin production by Penicillium chrysogenum". Fungal Genetics and Biology. 42 (2): 154–164. doi:10.1016/j.fgb.2004.10.010. PMID   15670713.
  24. ↑ Cantwell, C. A.; Beckmann, R. J.; Dotzlaf, J. E.; Fisher, D. L.; Skatrud, P. L.; Yeh, W. K.; Queener, S. W. (1990). "Cloning and expression of a hybrid Streptomyces clavuligerus cefE gene in Penicillium chrysogenum". Current Genetics. 17 (3): 213–221. doi:10.1007/BF00312612. PMID   2111228. S2CID   9230950.
  25. ↑ Ferrero, M. A.; Reglero, A.; Martín-Villacorta, J.; Fernández-Cañón, J. M.; Luengo, J. M. (1990). "Biosynthesis of benzylpenicillin (G), phenoxymethylpenicillin (V) and octanoylpenicillin (K) from glutathione S-derivatives". The Journal of Antibiotics. 43 (6): 684–691. doi: 10.7164/antibiotics.43.684 . PMID   2166024.
  26. ↑ Winkle, Walton Van; Herwick, Robert P. (1945). "Penicillin—a review*". Journal of the American Pharmaceutical Association. 34 (4): 97–109. doi:10.1002/jps.3030340402. PMC   3802448 .
  27. ↑ Lobanovska, Mariya; Pilla, Giulia (2017). "Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future?". The Yale Journal of Biology and Medicine. 90 (1): 135–145. PMC   5369031 . PMID   28356901.
  28. ↑ Bush, K (2004). "Antibacterial drug discovery in the 21st century". Clinical Microbiology and Infection. 10: 10–17. doi: 10.1111/j.1465-0691.2004.1005.x . PMID   15522035.
  29. ↑ Lobanovska, Mariya; Pilla, Giulia (2017). "Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future?". The Yale Journal of Biology and Medicine. 90 (1): 135–145. ISSN   1551-4056. PMC   5369031 . PMID   28356901.
  30. ↑ "Penicillin G Potassium Injection, USP" (PDF). US FDA. July 2016. Archived (PDF) from the original on 2021-04-01. Retrieved 2020-12-28.
  31. ↑ Weinstein, Louis; Lerner, Phillip I.; Chew, William H. (1964-09-10). "Clinical and Bacteriologic Studies of the Effect of Massive Doses of Penicillin G on Infections Caused by Gram-Negative Bacilli" . New England Journal of Medicine. 271 (11): 525–533. doi:10.1056/NEJM196409102711101. ISSN   0028-4793. PMID   14172468.
  32. ↑ Wright, Alan J. (1999-03-01). "The Penicillins" . Mayo Clinic Proceedings. 74 (3): 290–307. doi:10.4065/74.3.290. ISSN   0025-6196. PMID   10090000.
  33. ↑ Liu, Ling; Chen, Zhen; Liu, Wuyi; Ke, Xiang; Tian, Xiwei; Chu, Ju (2022-10-01). "Cephalosporin C biosynthesis and fermentation in Acremonium chrysogenum" . Applied Microbiology and Biotechnology. 106 (19): 6413–6426. doi:10.1007/s00253-022-12181-w. ISSN   1432-0614. PMID   36114850.
  34. ↑ Brakhage, Axel A.; Spröte, Petra; Al-Abdallah, Qusai; Gehrke, Alexander; Plattner, Hans; Tüncher, André (2004-10-04), Brakhage, A. A. (ed.), "Regulation of Penicillin Biosynthesis in Filamentous Fungi" , Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases, vol. 88, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 45–90, doi:10.1007/b99257, ISBN   978-3-540-22032-9, PMID   15719552 , retrieved 2025-07-11
  35. ↑ Brakhage, Axel A. (1998). "Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi". Microbiology and Molecular Biology Reviews. 62 (3): 547–585. doi:10.1128/MMBR.62.3.547-585.1998. ISSN   1092-2172. PMC   98925 . PMID   9729600.
  36. ↑ Harris, Diana M.; Westerlaken, Ilja; Schipper, Dick; van der Krogt, Zita A.; Gombert, Andreas K.; Sutherland, John; Raamsdonk, Leonie M.; van den Berg, Marco A.; et al. (2009). "Engineering of Penicillium chrysogenum for fermentative production of a novel carbamoylated cephem antibiotic precursor" . Metabolic Engineering. 11 (2): 125–137. doi:10.1016/j.ymben.2008.12.003. PMID   19271269.
  37. ↑ Iacovelli, Riccardo; Bovenberg, Roel A L; Driessen, Arnold J M (2021-08-24). "Nonribosomal peptide synthetases and their biotechnological potential in Penicillium rubens". Journal of Industrial Microbiology and Biotechnology. 48 (7–8) kuab045. doi:10.1093/jimb/kuab045. ISSN   1367-5435. PMC   8788816 . PMID   34279620.
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