Pentabromopseudilin

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Pentabromopseudilin
Pentabromopseudilin.png
Names
Preferred IUPAC name
2,4-Dibromo-6-(3,4,5-tribromo-1H-pyrrol-2-yl)phenol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C10H4Br5NO/c11-3-1-4(9(17)5(12)2-3)8-6(13)7(14)10(15)16-8/h1-2,16-17H
    Key: LXMNWKJHYOZUQL-UHFFFAOYSA-N
  • C1=C(C=C(C(=C1Br)O)C2=C(C(=C(N2)Br)Br)Br)Br
Properties
C10H4Br5NO
Molar mass 553.668 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pentabromopseudilin, the first reported marine microbial antibiotic,[ citation needed ] is a bioactive natural product that contains a highly halogenated 2-arrylpyrrole moiety. Pentabromopseudilin (PBP) is a unique hybrid bromophenol-bromopyrrole compound that is made up of over 70% bromine atoms, contributing to its potent bioactivity. PBP was first isolated from Pseudomonas bromoutilis, and has since been found to be produced by other marine microbes, including Alteromonas luteoviolaceus, Chromobacteria, and Pseudoalteromonas spp.

Contents

History

PBP was first isolated and reported in 1966, when Burkholder and colleagues identified an unusual, highly brominated pyrrole antibiotic that was produced from Thalassia -associated marine bacteria collected from tropical waters off La Parguera, Puerto Rico. [1] Early investigations from this first report pointed at intrigue in regards to the pyrrole's particularly potent activity against gram positive bacteria, namely the strains Staphylococcus aureus , Diplococcus pneumoniae and Streptococcus pyogenes. However, despite inhibition these strains at PBP drug concentrations of 0.0063 μg/ml, these promising preliminary findings failed to yield the same success in in vivo mouse therapeutic studies.

Biological activity

Of more than 20 classified pyrrole antibiotics, PBP is the most active member in its class, and demonstrates a high in vitro activity (IC50 = 0.1 μM) against methicillin-resistant Staphylococcus aureus (MRSA). [2] As such, it has a served as a model example of the potential significance of marine natural products drug discovery as an effective resource in the face of "superbug" antibiotic resistance. [3] [4] Other than being a potent antibiotic, PBP also demonstrates a wide variety of in vitro biological functions including antitumor activity, antifungal activity, myosin inhibition, [5] human lipoxygenase inhibition, [6] and phytotoxicity. [7]

Biosynthesis

The biosynthesis of PBP was first shown through isotope feeding studies, and then biochemically when genomic data of PBP-producing strains became readily available.

Early isotope feeding studies

The first investigations seeking to understand PBP biosynthesis was targeted by identifying PBP building blocks by feeding isotopically-labeled putative precursors of the phenol and pyrrole rings to PBP-producing bacteria. Identification of isotope labels being incorporated in the natural product would shed light on biosynthetic steps preceding the formation of PBP.

In 1994, a feeding experiment study conducted on Alteromonas luteoviolaceus demonstrated that the phenol ring of PBP is derived from the shikimate pathway. [8] In this work, general precursors that were labeled with 13C were fed to A. luteoviolaceus cultures after inoculation. It was found that the incorporation of a variety of glucose labels ([2-13C]-, [1,2-13C2]-, and [3-13C]), indicated that the PBP benzene ring is derived from carbohydrate metabolism and have occurred through erythrose 4-phosphate. From these results indicating a shikimic acid derivation, it was further deduced that p-hydroxybenzoic acid (4-HBA) be a plausible precursor for PBP's phenol group. [9] This was indeed proven when isotopically labeled 4-HBA was observed to be incorporated into the phenol ring of PBP at >80%. [10] Despite this groundbreaking study, no 13C incorporation was observed in the pyrrole ring of PBP.

In 2004, a follow-up study described the PBP pyrrole ring as derived from L-proline. [11] This work involved an isotope-feeding study involving 21 different Alteromonas luteoviolaceus culture medias that were introduced with labeled [5-13C]proline in addition to tyrosine, histidine, ornithine, glycine, potassium bromide (KBr), and PBP. From this feeding experiment, it was determined that the overall enrichment of PBP had increased by 60%- indicating that proline had directly converted into the pyrrole ring.

Genetic basis for pentabromopseudilin biosynthesis

Bmp pathway for brominated marine pyrroles and phenols, for pentabromopseudilin Bmp pathway.png
Bmp pathway for brominated marine pyrroles and phenols, for pentabromopseudilin

The biosynthesis of pentabromopseudilin, among other halopyrroles, has been elucidated via the identification of the conserved brominated marine pyrroles/phenols (bmp) pathway first identified in the marine bacteria, P. luteoviolacea 2ta16 and P. phenolica O-BC30. [12] The bmp pathway describes a bi-modular scheme for polybrominated marine microbial natural products production. In the first module, the bromophenol moiety of PBP is first assembled from a chorismate precursor which is then converted by Bmp6, a chorismate lyase (CL), to yield 4-HBA. 4-HBA is then di-halogenated by the flavin-dependent halogenase, Bmp5 (Hal), to yield 2,3-dibromophenol.

Consistent with earlier isotopic studies, the PBP halopyrrole biosynthesis via the bmp pathway begins with L-proline. In this module, L-proline is acylated to the acyl carrier protein domain of Bmp1 (ACP-thioesterase (TE) di-domain protein) by the proline adenyl transferase Bmp4 (A). The flavin-dependent dehydrogenase, Bmp3 (DH), then oxidizes the prolyl ring to a pyrrole. [13] The loaded protein is then tri-brominated with the flavin-dependent halogenase, Bmp2 (Hal), becoming 2,3,4,5-tetrabromopyrrole. Next, Bmp8 (D), a unique thioredoxin-like dehalogenase, removes the C-2 bromine of tetrabromopyrrole, [14] which then allows for coupling to the previously described 2,4-dibromophenol via the cytochrome P450 enzyme, Bmp7 (C).

Related Research Articles

Beta-lactam

A beta-lactam (β-lactam) ring is a four-membered lactam. A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines as manifested in many β-Lactam antibiotics Up to 1970, most β-lactam research was concerned with the penicillin and cephalosporin groups, but since then, a wide variety of structures have been described.

Penicillin Group of antibiotics derived from Penicillium fungi

Penicillins are a group of antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are chemically synthesised from naturally-produced penicillins. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are members of the β-lactam antibiotics. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

Beta-lactam antibiotics Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3. Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as heme.

Methicillin Antibiotic medication

Methicillin, also known as meticillin, is a narrow-spectrum β-lactam antibiotic of the penicillin class.

Anisomycin Chemical compound

Anisomycin, also known as flagecidin, is an antibiotic produced by Streptomyces griseolus which inhibits eukaryotic protein synthesis. Partial inhibition of DNA synthesis occurs at anisomycin concentrations that effect 95% inhibition of protein synthesis. Anisomycin can activate stress-activated protein kinases, MAP kinase and other signal transduction pathways.

Bacteriochlorophyll Chemical compound

Bacteriochlorophylls (BChl) are photosynthetic pigments that occur in various phototrophic bacteria. They were discovered by C. B. van Niel in 1932. They are related to chlorophylls, which are the primary pigments in plants, algae, and cyanobacteria. Organisms that contain bacteriochlorophyll conduct photosynthesis to sustain their energy requirements, but do not produce oxygen as a byproduct. They use wavelengths of light not absorbed by plants or cyanobacteria. Replacement of Mg2+
 with protons gives bacteriophaeophytin (BPh), the phaeophytin form.

Filamentation

Filamentation, also termed conditional filamentation, is the anomalous growth of certain bacteria, such as Escherichia coli, in which cells continue to elongate but do not divide. The cells that result from elongation without division have multiple chromosomal copies. In the absence of antibiotics or other stressors, filamentation occurs at a low frequency in bacterial populations, the increased cell length protecting bacteria from protozoan predation and neutrophil phagocytosis by making ingestion of the cells more difficult. Filamentation is also thought to protect bacteria from antibiotics, and is associated with other aspects of bacterial virulence such as biofilm formation. The number and length of filaments within a bacterial population increases when the bacteria are treated with various chemical and physical agents. Some of the key genes involved in filamentation in E. coli include sulA and minCD.

A23187 Chemical compound

A23187 is a mobile ion-carrier that forms stable complexes with divalent cations. A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of Streptomyceschartreusensis.

Penicillin-binding proteins

Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.

Prodigiosin Chemical compound

Prodigiosin is the red dyestuff produced by many strains of the bacterium Serratia marcescens, as well as other Gram-negative, gamma proteobacteria such as Vibrio psychroerythrus and Hahella chejuensis. It is responsible for the pink tint occasionally found in grime that accumulates on porcelain surfaces such as bathtubs, sinks, and toilet bowls. It is in the prodiginines family of compounds which are produced in some Gram-negative gamma proteobacteria, as well as select Gram-positive Actinobacteria. The name prodigiosin is derived from prodigious.

Thienamycin Chemical compound

Thienamycin is one of the most potent naturally produced antibiotics known thus far, discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes. Thienamycin is a zwitterion at pH 7.

Clavam Class of antibiotics

Clavams are a class of antibiotics. This antibiotic is derived from Streptomyces clavuligerus NRRL 3585. Clavam is produced to form a new β-lactam antibiotic. This class is divided into the clavulanic acid class and the 5S clavams class. Clavulanic acid is a broad-spectrum antibiotic and 5S clavams may have anti-fungal properties. They are similar to penams, but with an oxygen substituted for the sulfur. Thus, they are also known as oxapenams.

Streptogramin A is a group of antibiotics within the larger family of antibiotics known as streptogramins. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds while group B antibiotics are depsipeptides. While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

Bacterial morphological plasticity refers to changes in the shape and size that bacterial cells undergo when they encounter stressful environments. Although bacteria have evolved complex molecular strategies to maintain their shape, many are able to alter their shape as a survival strategy in response to protist predators, antibiotics, the immune response, and other threats.

Tambjamine Chemical compound

Tambjamines are a group of natural products that are structurally related to the prodiginines. They are enamine derivatives of 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC).

Lipid II Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

Pyoluteorin

Pyoluteorin is a natural antibiotic that is biosynthesized from a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathway. Pyoluteorin was first isolated in the 1950s from Pseudomonas aeruginosa strains T359 and IFO 3455 and was found to be toxic against oomycetes, bacteria, fungi, and against certain plants. Pyoluteorin is most notable for its toxicity against the oomycete Pythium ultimum, which is a plant pathogen that causes a global loss in agriculture. Currently, pyoluteorin derivatives are being studied as an Mcl-1 antagonist in order to target cancers that have elevated Mcl-1 levels.

Prodiginines

The prodiginines are a family of red tripyrrole dyestuffs produced by Gammaproteobacteria as well as some Actinomycetota. The group is named after prodigiosin (prodiginine) and is biosynthesized through a common set of enzymes. They are interesting due to their history and their varied biological activity.

References

  1. ↑ Burkholder, Paul R.; Pfister, Robert M.; Leitz, Frederick H. (1 July 1966). "Production of a Pyrrole Antibiotic by a Marine Bacterium1". Applied Microbiology. 14 (4): 649–653. doi:10.1128/AM.14.4.649-653.1966. ISSN   0003-6919. PMC   546803 . PMID   4380876.
  2. ↑ Schwalm, Cristiane S.; de Castro, Ilton B.D.; Ferrari, Jailton; de Oliveira, Fábio L.; Aparicio, Ricardo; Correia, Carlos Roque D. (March 2012). "Synthesis of pentabromopseudilin and other arylpyrrole derivatives via Heck arylations". Tetrahedron Letters. 53 (13): 1660–1663. doi: 10.1016/j.tetlet.2012.01.086 .
  3. ↑ LAATSCH, Hartmut; RENNEBERG, Bernd; HANEFELD, Ulf; KELLNER, Michael; PUDLEINER, Heinz; HAMPRECHT, Gerhard; KRAEMER, Hans-Peter; ANKE, Heidrun (1995). "Structure-Activity Relationships of Phenyl- and Benzoylpyrroles". Chemical & Pharmaceutical Bulletin. 43 (4): 537–546. doi: 10.1248/cpb.43.537 . PMID   7600609.
  4. ↑ Rahman, Hafizur; Austin, Brian; Mitchell, Wilfrid J.; Morris, Peter C.; Jamieson, Derek J.; Adams, David R.; Spragg, Andrew Mearns; Schweizer, Michael (5 March 2010). "Novel Anti-Infective Compounds from Marine Bacteria". Marine Drugs. 8 (3): 498–518. doi: 10.3390/md8030498 . PMC   2857357 . PMID   20411112.
  5. ↑ Fedorov, Roman; Böhl, Markus; Tsiavaliaris, Georgios; Hartmann, Falk K; Taft, Manuel H; Baruch, Petra; Brenner, Bernhard; Martin, René; Knölker, Hans-Joachim; Gutzeit, Herwig O; Manstein, Dietmar J (4 January 2009). "The mechanism of pentabromopseudilin inhibition of myosin motor activity". Nature Structural & Molecular Biology. 16 (1): 80–88. doi:10.1038/nsmb.1542. PMID   19122661. S2CID   17109386.
  6. ↑ Ohri, Rachana V.; Radosevich, Alexander T.; Hrovat, K. James; Musich, Christine; Huang, David; Holman, Theodore R.; Toste, F. Dean (June 2005). "A Re(V)-Catalyzed C−N Bond-Forming Route to Human Lipoxygenase Inhibitors". Organic Letters. 7 (12): 2501–2504. doi:10.1021/ol050897a. PMID   15932233.
  7. ↑ Schwalm, Cristiane S.; de Castro, Ilton B.D.; Ferrari, Jailton; de Oliveira, Fábio L.; Aparicio, Ricardo; Correia, Carlos Roque D. (March 2012). "Synthesis of pentabromopseudilin and other arylpyrrole derivatives via Heck arylations". Tetrahedron Letters. 53 (13): 1660–1663. doi: 10.1016/j.tetlet.2012.01.086 .
  8. ↑ Hanefeld, Ulf; Floss, Heinz G.; Laatsch, Hartmut (July 1994). "Biosynthesis of the marine antibiotic pentabromopseudilin. Part 1. The benzene ring". The Journal of Organic Chemistry. 59 (13): 3604–3608. doi:10.1021/jo00092a020.
  9. ↑ Atta-ur-Rahman, edited by (2000). Bioactive natural products (1. ed.). Amsterdam: Elsevier. ISBN   978-0-444-50469-2.{{cite book}}: |first1= has generic name (help)
  10. ↑ Hanefeld, Ulf; Floss, Heinz G.; Laatsch, Hartmut (July 1994). "Biosynthesis of the marine antibiotic pentabromopseudilin. Part 1. The benzene ring". The Journal of Organic Chemistry. 59 (13): 3604–3608. doi:10.1021/jo00092a020.
  11. ↑ PESCHKE, Jörg D.; HANEFELD, Ulf; LAATSCH, Hartmut (22 May 2014). "Biosynthesis of the Marine Antibiotic Pentabromopseudilin. 2. The Pyrrole Ring". Bioscience, Biotechnology, and Biochemistry. 69 (3): 628–630. doi: 10.1271/bbb.69.628 . PMID   15784994.
  12. ↑ Agarwal, Vinayak; El Gamal, Abrahim A; Yamanaka, Kazuya; Poth, Dennis; Kersten, Roland D; Schorn, Michelle; Allen, Eric E; Moore, Bradley S (29 June 2014). "Biosynthesis of polybrominated aromatic organic compounds by marine bacteria". Nature Chemical Biology. 10 (8): 640–647. doi:10.1038/NCHEMBIO.1564. PMC   4104138 . PMID   24974229.
  13. ↑ El Gamal, Abrahim; Agarwal, Vinayak; Diethelm, Stefan; Rahman, Imran; Schorn, Michelle A.; Sneed, Jennifer M.; Louie, Gordon V.; Whalen, Kristen E.; Mincer, Tracy J.; Noel, Joseph P.; Paul, Valerie J.; Moore, Bradley S. (5 April 2016). "Biosynthesis of coral settlement cue tetrabromopyrrole in marine bacteria by a uniquely adapted brominase–thioesterase enzyme pair". Proceedings of the National Academy of Sciences. 113 (14): 3797–3802. Bibcode:2016PNAS..113.3797E. doi: 10.1073/pnas.1519695113 . PMC   4833250 . PMID   27001835.
  14. ↑ El Gamal, Abrahim; Agarwal, Vinayak; Rahman, Imran; Moore, Bradley S. (12 October 2016). "Enzymatic Reductive Dehalogenation Controls the Biosynthesis of Marine Bacterial Pyrroles". Journal of the American Chemical Society. 138 (40): 13167–13170. doi:10.1021/jacs.6b08512. PMC   5201201 . PMID   27676265.
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