Plantazolicin (PZN) is a natural

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

produced by the

gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...

soil bacterium ''Bacillus velezensis'' FZB42 (previously '' Bacillus amyloliquefaciens'' FZB42). PZN has specifically been identified as a selective bactericidal agent active against ''

Bacillus anthracis ''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent (obligate) pathogen within the genus ''Bacillus''. Its infection is a ty ...

'', the causative agent of

anthrax Anthrax is an infection caused by the bacterium '' Bacillus anthracis'' or ''Bacillus cereus'' biovar ''anthracis''. Infection typically occurs by contact with the skin, inhalation, or intestinal absorption. Symptom onset occurs between one ...

. This

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...

is a ribosomally synthesized and post-translationally modified

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

(RiPP); it can be classified further as a thiazole/oxazole-modified microcin (TOMM) or a linear

azole Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e. nitrogen, sulfur, or oxygen) as part of the ring. Their names originate from the Hantzsch–Widman nomenclature. Th ...

-containing

(LAP). The significance of PZN stems from its narrow-spectrum antibiotic activity. Most antibiotics in clinical use are

broad-spectrum A broad-spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are used when a bacterial in ...

, acting against a wide variety of bacteria, and

antibiotic resistance Antimicrobial resistance (AMR or AR) occurs when microbes evolve mechanisms that protect them from antimicrobials, which are drugs used to treat infections. This resistance affects all classes of microbes, including bacteria (antibiotic resis ...

to these drugs is common. In contrast, PZN is antibacterial against only a small number of species, including ''

''. __TOC__

History

The

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

for the

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

of PZN were first reported in 2008. The natural product was then isolated in 2011 from '' Bacillus amyloliquefaciens''. The structure of PZN was solved later that year by two independent research groups, primarily through high-resolution

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

and

NMR spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique based on re-orientation of atomic nuclei with non-zero nuclear spins in an external magnetic f ...

. In 2013, various biomimetic chemical synthesis studies of PZN were reported, including a

total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...

Biosynthesis

In bacteria, plantazolicin (PZN) is synthesized first as an unmodified peptide via

translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...

at the

ribosome Ribosomes () are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order s ...

. A series of

enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...

then chemically alter the peptide to install its post-translational modifications, including several

heterocycle A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

s and an N-terminal

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

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 Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

and

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

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 A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do ...

contained in the biosynthetic

gene cluster A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...

. 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 ''Bacillus pumilus'' is a Gram-positive, Aerobic organism, aerobic, spore-forming bacillus commonly found in soil. ''Bacillus pumilus'' spores—with the exception of mutant strain ATCC 7061—generally show high resistance to environmental stre ...

'', '' Clavibacter michiganensis subsp. sepedonicus'', ''

Corynebacterium urealyticum ''Corynebacterium urealyticum'' is a bacterial species of the genus ''Corynebacterium''. It is not commonly found in healthy people. It is, however, an important isolate when found in conjunction with a urinary tract infection. In contrast to ac ...

'', and'' Brevibacterium linens '' have been identified with similar gene clusters that have the potential to produce PZN-like molecules.

References

{{reflist Bactericides Antibiotics Peptides Oxazolines Oxazoles Thiazoles