Plantazolicin Explained

Plantazolicin (PZN) is a natural antibiotic produced by the gram-positive soil bacterium Bacillus velezensis FZB42^[1] (previously Bacillus amyloliquefaciens FZB42).^[2] PZN has specifically been identified as a selective bactericidal agent active against Bacillus anthracis, the causative agent of anthrax. This natural product is a ribosomally synthesized and post-translationally modified peptide (RiPP); it can be classified further as a thiazole/oxazole-modified microcin (TOMM) or a linear azole-containing peptide (LAP).^[3]

The significance of PZN stems from its narrow-spectrum antibiotic activity. Most antibiotics in clinical use are broad-spectrum, acting against a wide variety of bacteria, and antibiotic resistance to these drugs is common. In contrast, PZN is antibacterial against only a small number of species, including Bacillus anthracis.

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History

The genes for the biosynthesis of PZN were first reported in 2008.^[4] The natural product was then isolated in 2011 from Bacillus amyloliquefaciens.^[5] The structure of PZN was solved later that year by two independent research groups, primarily through high-resolution mass spectrometry and NMR spectroscopy.^{[6] [7]} In 2013, various biomimetic chemical synthesis studies of PZN were reported, including a total synthesis.^[8]

Biosynthesis

In bacteria, plantazolicin (PZN) is synthesized first as an unmodified peptide via translation at the ribosome. A series of enzymes then chemically alter the peptide to install its post-translational modifications, including several azole heterocycles and an N-terminal amine dimethylation.

Specifically, during the biosynthesis of PZN in B. velezensis, a ribosomally-synthesized precursor peptide undergoes extensive post-translational modification, including cyclodehydrations and dehydrogenations, catalyzed by a trimeric enzyme complex. This process converts cysteine and serine/threonine residues into thiazole and (methyl)oxazole heterocycles (as seen to the right).

The exact mechanism of the association of the trimeric enzyme complex with the N-terminal leader peptide region is not yet understood; however, it is thought that the leader peptide is cleaved from the core peptide putatively by the peptidase contained in the biosynthetic gene cluster.^[9] Following leader peptide removal, the newly formed N-terminus undergoes methylation to yield an . This final modification results in mature PZN.

Other organisms such as Bacillus pumilus, Clavibacter michiganensis subsp. sepedonicus, Corynebacterium urealyticum , and Brevibacterium linens have been identified with similar gene clusters that have the potential to produce PZN-like molecules.^[7]

Notes and References

1. https://www.uniprot.org/proteomes/UP000001120 Proteomes - Bacillus velezensis (strain DSM 23117 / BGSC 10A6 / FZB42) (Bacillus amyloliquefaciens subsp. plantarum)
2. Fan. Ben. Wang. Cong. Song. Xiaofeng. Ding. Xiaolei. Wu. Liming. Wu. Huijun. Gao. Xuewen. Borriss. Rainer. 2018-10-16. Bacillus velezensis FZB42 in 2018: The Gram-Positive Model Strain for Plant Growth Promotion and Biocontrol. Frontiers in Microbiology. 9. 2491. 10.3389/fmicb.2018.02491. 1664-302X. 6198173. 30386322. free.
3. 10.1039/c2np20085f . 23165928 . 3954855 . Ribosomally synthesized and post-translationally modified peptide natural products: Overview and recommendations for a universal nomenclature . Nat. Prod. Rep. . 30 . 1 . 108–160 . 2013 . Arnison . Paul G. . Bibb . Mervyn J. . Bierbaum . Gabriele . Bowers . Albert A. . Bugni . Tim S. . Bulaj . Grzegorz . Camarero . Julio A. . Campopiano . Dominic J. . Challis . Gregory L. . Clardy . Jon . Cotter . Paul D. . Craik . David J. . Dawson . Michael . Dittmann . Elke . Donadio . Stefano . Dorrestein . Pieter C. . Entian . Karl-Dieter . Fischbach . Michael A. . Garavelli . John S. . Göransson . Ulf . Gruber . Christian W. . Haft . Daniel H. . Hemscheidt . Thomas K. . Hertweck . Christian . Hill . Colin . Horswill . Alexander R. . Jaspars . Marcel . Kelly . Wendy L. . Klinman . Judith P. . Kuipers . Oscar P. . 29 .
4. 10.1073/pnas.0801338105 . 18375757 . 2311365 . Discovery of a widely distributed toxin biosynthetic gene cluster . Proceedings of the National Academy of Sciences . 105 . 15 . 5879–5884 . 2008 . Lee . S. W. . Mitchell . D. A. . Markley . A. L. . Hensler . M. E. . Gonzalez . D. . Wohlrab . A. . Dorrestein . P. C. . Nizet . V. . Dixon . J. E. . free .
5. 10.1128/JB.00784-10 . 20971906 . 3019963 . Plantazolicin, a Novel Microcin B17/Streptolysin S-Like Natural Product from Bacillus amyloliquefaciens FZB42 . Journal of Bacteriology . 193 . 1 . 215–224 . 2011 . Scholz . R. . Molohon . K. J. . Nachtigall . J. . Vater . J. . Markley . A. L. . Sussmuth . R. D. . Mitchell . D. A. . Borriss . R. .
6. 10.1021/ol200809m . 21568297 . Plantazolicin a and B: Structure Elucidation of Ribosomally Synthesized Thiazole/Oxazole Peptides from Bacillus amyloliquefaciensFZB42 . Organic Letters . 13 . 12 . 2996–2999 . 2011 . Kalyon . Bahar . Helaly . Soleiman E. . Scholz . Romy . Nachtigall . Jonny . Vater . Joachim . Borriss . Rainer . SüSsmuth . Roderich D. .
7. 10.1021/cb200339d . 21950656 . 3241860 . Structure Determination and Interception of Biosynthetic Intermediates for the Plantazolicin Class of Highly Discriminating Antibiotics . ACS Chemical Biology . 6 . 12 . 1307–1313 . 2011 . Molohon . Katie J. . Melby . Joel O. . Lee . Jaeheon . Evans . Bradley S. . Dunbar . Kyle L. . Bumpus . Stefanie B. . Kelleher . Neil L. . Mitchell . Douglas A. .
8. 10.1002/anie.201302266 . 23761292 . Total Synthesis of the Ribosomally Synthesized Linear Azole-Containing Peptide Plantazolicin a from Bacillus amyloliquefaciens . Angewandte Chemie International Edition . 52 . 36 . 9518–9523 . 2013 . Banala . Srinivas . Ensle . Paul . Süssmuth . Roderich D. .
9. 10.1016/j.cbpa.2011.02.027 . 21429787 . 3947797 . Thiazole/Oxazole-modified microcins: Complex natural products from ribosomal templates . Current Opinion in Chemical Biology . 15 . 3 . 369–378 . 2011 . Melby . Joel O. . Nard . Nathan J. . Mitchell . Douglas A. .