Plantazolicin
{{short description|Chemical compound}}
{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 386192575
| ImageFile=PZN-ACS.png
| ImageSize=300px
| OtherNames=plantazolicin A, PZN
|Section1={{Chembox Identifiers
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| CASNo=1354655-37-0
| ChemSpiderID = 57643663
| PubChem = 139031015
| StdInChI = 1S/C63H69N17O13S2/c1-11-28(3)43(74-51(83)46-31(6)93-59(77-46)47-32(7)91-56(78-47)41-27-95-61(73-41)48-33(8)92-57(79-48)40-26-94-60(72-40)42(80(9)10)19-16-20-66-63(64)65)49(81)75-44(29(4)12-2)58-71-38(24-89-58)54-69-36(22-87-54)52-68-37(23-86-52)53-70-39(25-88-53)55-76-45(30(5)90-55)50(82)67-35(62(84)85)21-34-17-14-13-15-18-34/h13-15,17-18,22-30,35,42-45H,11-12,16,19-21H2,1-10H3,(H,67,82)(H,74,83)(H,75,81)(H,84,85)(H4,64,65,66)/t28-,29-,30+,35-,42-,43-,44-,45-/m0/s1
| StdInChIKey = SKALCVOFYPVXLA-UCYFTIMGSA-N
| SMILES=CC[C@H](C)[C@@H](c1nc(co1)c2nc(co2)c3nc(co3)c4nc(co4)C5=N[C@@H](C(O5)C)C(=O)N[C@@H](Cc6ccccc6)C(=O)O)NC(=O)C([C@@H](C)CC)NC(=O)c7c(oc(n7)c8c(oc(n8)c9csc(n9)c1c(oc(n1)c1csc(n1)[C@H](CCCNC(=N)N)N(C)C)C)C)C
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|Section2={{Chembox Properties
| C=63 | H=69 | N=17 | O=13 | S=2
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|Section3={{Chembox Hazards
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Plantazolicin (PZN) is a natural antibiotic produced by the gram-positive soil bacterium Bacillus velezensis FZB42[https://www.uniprot.org/proteomes/UP000001120 Proteomes - Bacillus velezensis (strain DSM 23117 / BGSC 10A6 / FZB42) (Bacillus amyloliquefaciens subsp. plantarum)] (previously Bacillus amyloliquefaciens FZB42).{{Cite journal|last1=Fan|first1=Ben|last2=Wang|first2=Cong|last3=Song|first3=Xiaofeng|last4=Ding|first4=Xiaolei|last5=Wu|first5=Liming|last6=Wu|first6=Huijun|last7=Gao|first7=Xuewen|last8=Borriss|first8=Rainer|date=2018-10-16|title=Bacillus velezensis FZB42 in 2018: The Gram-Positive Model Strain for Plant Growth Promotion and Biocontrol|journal=Frontiers in Microbiology|volume=9|pages=2491|doi=10.3389/fmicb.2018.02491|issn=1664-302X|pmc=6198173|pmid=30386322|doi-access=free}} 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).{{Cite journal | doi = 10.1039/c2np20085f | pmid = 23165928 | pmc = 3954855 | title = Ribosomally synthesized and post-translationally modified peptide natural products: Overview and recommendations for a universal nomenclature | journal = Nat. Prod. Rep. | volume = 30 | issue = 1 | pages = 108–160 | year = 2013 | last1 = Arnison | first1 = Paul G. | last2 = Bibb | first2 = Mervyn J. | last3 = Bierbaum | first3 = Gabriele | last4 = Bowers | first4 = Albert A. | last5 = Bugni | first5 = Tim S. | last6 = Bulaj | first6 = Grzegorz | last7 = Camarero | first7 = Julio A. | last8 = Campopiano | first8 = Dominic J. | last9 = Challis | first9 = Gregory L. | last10 = Clardy | first10 = Jon | last11 = Cotter | first11 = Paul D. | last12 = Craik | first12 = David J. | last13 = Dawson | first13 = Michael | last14 = Dittmann | first14 = Elke | last15 = Donadio | first15 = Stefano | last16 = Dorrestein | first16 = Pieter C. | last17 = Entian | first17 = Karl-Dieter | last18 = Fischbach | first18 = Michael A. | last19 = Garavelli | first19 = John S. | last20 = Göransson | first20 = Ulf | last21 = Gruber | first21 = Christian W. | last22 = Haft | first22 = Daniel H. | last23 = Hemscheidt | first23 = Thomas K. | last24 = Hertweck | first24 = Christian | last25 = Hill | first25 = Colin | last26 = Horswill | first26 = Alexander R. | last27 = Jaspars | first27 = Marcel | last28 = Kelly | first28 = Wendy L. | last29 = Klinman | first29 = Judith P. | last30 = Kuipers | first30 = Oscar P. | display-authors = 29 }}
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.{{cn|date=February 2023}}
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History
The genes for the biosynthesis of PZN were first reported in 2008.{{Cite journal | doi = 10.1073/pnas.0801338105 | pmid = 18375757 | pmc = 2311365 | title = Discovery of a widely distributed toxin biosynthetic gene cluster | journal = Proceedings of the National Academy of Sciences | volume = 105 | issue = 15 | pages = 5879–5884 | year = 2008 | last1 = Lee | first1 = S. W. | last2 = Mitchell | first2 = D. A. | last3 = Markley | first3 = A. L. | last4 = Hensler | first4 = M. E. | last5 = Gonzalez | first5 = D. | last6 = Wohlrab | first6 = A. | last7 = Dorrestein | first7 = P. C. | last8 = Nizet | first8 = V. | last9 = Dixon | first9 = J. E. | doi-access = free }} The natural product was then isolated in 2011 from Bacillus amyloliquefaciens.{{Cite journal | doi = 10.1128/JB.00784-10 | pmid = 20971906 | pmc = 3019963 | title = Plantazolicin, a Novel Microcin B17/Streptolysin S-Like Natural Product from Bacillus amyloliquefaciens FZB42 | journal = Journal of Bacteriology | volume = 193 | issue = 1 | pages = 215–224 | year = 2011 | last1 = Scholz | first1 = R. | last2 = Molohon | first2 = K. J. | last3 = Nachtigall | first3 = J. | last4 = Vater | first4 = J. | last5 = Markley | first5 = A. L. | last6 = Sussmuth | first6 = R. D. | last7 = Mitchell | first7 = D. A. | last8 = Borriss | first8 = R. }} The structure of PZN was solved later that year by two independent research groups, primarily through high-resolution mass spectrometry and NMR spectroscopy.{{Cite journal | doi = 10.1021/ol200809m | pmid = 21568297 | title = Plantazolicin a and B: Structure Elucidation of Ribosomally Synthesized Thiazole/Oxazole Peptides from Bacillus amyloliquefaciensFZB42 | journal = Organic Letters | volume = 13 | issue = 12 | pages = 2996–2999 | year = 2011 | last1 = Kalyon | first1 = Bahar | last2 = Helaly | first2 = Soleiman E. | last3 = Scholz | first3 = Romy | last4 = Nachtigall | first4 = Jonny | last5 = Vater | first5 = Joachim | last6 = Borriss | first6 = Rainer | last7 = SüSsmuth | first7 = Roderich D. }}{{Cite journal | doi = 10.1021/cb200339d | pmid = 21950656 | pmc = 3241860 | title = Structure Determination and Interception of Biosynthetic Intermediates for the Plantazolicin Class of Highly Discriminating Antibiotics | journal = ACS Chemical Biology | volume = 6 | issue = 12 | pages = 1307–1313 | year = 2011 | last1 = Molohon | first1 = Katie J. | last2 = Melby | first2 = Joel O. | last3 = Lee | first3 = Jaeheon | last4 = Evans | first4 = Bradley S. | last5 = Dunbar | first5 = Kyle L. | last6 = Bumpus | first6 = Stefanie B. | last7 = Kelleher | first7 = Neil L. | last8 = Mitchell | first8 = Douglas A. }} In 2013, various biomimetic chemical synthesis studies of PZN were reported, including a total synthesis.{{Cite journal | doi = 10.1002/anie.201302266 | pmid = 23761292 | title = Total Synthesis of the Ribosomally Synthesized Linear Azole-Containing Peptide Plantazolicin a from Bacillus amyloliquefaciens | journal = Angewandte Chemie International Edition | volume = 52 | issue = 36 | pages = 9518–9523 | year = 2013 | last1 = Banala | first1 = Srinivas | last2 = Ensle | first2 = Paul | last3 = Süssmuth | first3 = Roderich D. }}
Biosynthesis
File:PZN-biosynthesis.png 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.{{cn|date=February 2023}}
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.{{Cite journal | doi = 10.1016/j.cbpa.2011.02.027 | pmid = 21429787 | pmc = 3947797 | title = Thiazole/Oxazole-modified microcins: Complex natural products from ribosomal templates | journal = Current Opinion in Chemical Biology | volume = 15 | issue = 3 | pages = 369–378 | year = 2011 | last1 = Melby | first1 = Joel O. | last2 = Nard | first2 = Nathan J. | last3 = Mitchell | first3 = Douglas A. }} Following leader peptide removal, the newly formed N-terminus undergoes methylation to yield an {{chem name|Nα,Nα-dimethylarginine}}. This final modification results in mature PZN.{{cn|date=February 2023}}
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.