Platensimycin, a metabolite of '' Streptomyces platensis'', is an antibiotic, which act by blocking enzymes (β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/ II (FabF/B)).

History

Platensimycin was first isolated from a strain of ''Streptomyces platensis'' by workers at Merck. Screens of 250,000 natural product extracts (83,000 strains in three growth conditions) led to the identification of a potent and selective small molecule from a strain of Streptomyces platensis recovered from a soil sample collected in South Africa. The identification process was carried out using a two-plate system in which control organisms were compared to cells expressing FabF antisense RNA. This method uses a combination of target-based whole-cell and biochemical assays, allowing compounds to be detected at concentrations that would be too low to detect using whole cell assays. The molecule they identified, platensimycin (C24H27NO7, relative

molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quanti ...

441.47), comprises two distinct structural elements connected by an amide bond. The

Merck Group The Merck Group, branded and commonly known as Merck, is a German multinational science and technology company headquartered in Darmstadt, with about 60,000 employees and present in 66 countries. The group includes around 250 companies; the ma ...

showed that platensimycin has potent, broad-spectrum Gram-positive activity ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' and exhibits no

cross-resistance Cross-resistance is when something develops resistance to several substances that have a similar mechanism of action. For example, if a certain type of bacteria develops resistance to one antibiotic, that bacteria will also have resistance to sev ...

to other key

antibiotic-resistant Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...

bacteria including

Methicillin-resistant Staphylococcus aureus Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of '' Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in human ...

(MRSA),

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...

-intermediate S. aureus, vancomycin-resistant Enterococci, and

linezolid Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, v ...

-resistant and

macrolide The Macrolides are a class of natural products that consist of a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered. Ma ...

-resistant

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

s. As confirmed by

total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...

racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

platensimycin, its structure consists of a 3-amino- 2,4-dihydroxybenzoic acid polar part linked through an amide bond to a

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

tetracyclic

ketolide Ketolides are antibiotics belonging to the macrolide group. Ketolides are derived from erythromycin by substituting the cladinose sugar with a keto-group and attaching a cyclic carbamate group in the lactone ring. These modifications give keto ...

Clinical use

Platensimycin is an

experimental drug An experimental drug is a medicinal product (a drug or vaccine) that has not yet received approval from governmental regulatory authorities for routine use in human or veterinary medicine. A medicinal product may be approved for use in one diseas ...

in preclinical trials involving MRSA in a

mouse model A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...

. Platensimycin is an effective antibiotic ''in vivo'' when continuously administered to cells. Efficacy is reduced when administered by more conventional means.

Clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s have been delayed. A variety of modifications have been investigated. and increase the activity of platensimycin.

Biosynthesis

Biosynthesitic studies show that the benzoic ring is produced from pyruvate and acetate via the

TCA cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

, while the C-17 tetracyclic enone acid core is produced from the non-mevalonate

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...

pathway. The tetracyclic enone isotope labeling pattern observed is consistent with the biosynthesis of the tetracycle via the non-mevalonate terpenoid pathway. This pathway involves condensation of a

thiamine Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...

-activated acetyl group arising from the decarboxylation of pyruvate and

glyceraldehyde-3-phosphate Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, ...

followed by a transposition step. Since both pyruvate and glyceraldehyde-3-phosphate (also

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

) are part of the glycolytic pathway, varying levels of incorporation are expected. Thus, the terpenoid building blocks, dimethylallyl diphosphate and isopentenyl diphosphate, synthesized by the non-mevalonate pathway utilizing pyruvate and glyceraldehyde-3-phosphate, condense to form the diterpenoid

precursor Precursor or Precursors may refer to: * Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...

geranylgeranyl diphosphate that cyclizes to an intermediate which is related to (or derived from) ent-kaurene.

Oxidative cleavage Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions, because many reactions carr ...

of the

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betwee ...

of this intermediate would result in the loss of the terminal three carbons producing the C-17 tetracyclic enone acid unit. An N-acyltransferase reaction of tetracyclic enone and aminobenzoic acid would lead to platensimycin.

Mechanism of action

Platensimycin has shown good activity against a panel of Gram-positive bacteria, including various resistant strains. Platensimycin works by inhibiting beta-ketoacyl syntheses I/II (FabF/B), which are involved in the production of fatty acids required for bacterial cell membranes. It interferes with enzymes involved in the condensation steps in

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

biosynthesis, which Gram-positive bacteria need to biosynthesise cell membranes. Other enzymes in this pathway have similarly been proven as antibiotic targets, such as FabI, the enoyl-ACP (acyl carrier protein) reductase, which is inhibited by

isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For la ...

and related compounds and the

antiseptic An antiseptic (from Greek ἀντί ''anti'', "against" and σηπτικός ''sēptikos'', "putrefactive") is an antimicrobial substance or compound that is applied to living tissue/skin to reduce the possibility of infection, sepsis, or putre ...

agent

triclosan Triclosan (sometimes abbreviated as TCS) is an antibacterial and antifungal agent present in some consumer products, including toothpaste, soaps, detergents, toys, and surgical cleaning treatments. It is similar in its uses and mechanism of ac ...

. One proposed mechanism of action is that, firstly, the

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

group of FabF Cys163 is activated through the

dipole In physics, a dipole () is an electromagnetic phenomenon which occurs in two ways: *An electric dipole deals with the separation of the positive and negative electric charges found in any electromagnetic system. A simple example of this system ...

moment of helix N-alpha-3 which lowers the pKa. The

nucleophilicity In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

of the cysteine is enhanced by an

oxyanion hole An oxyanion hole is a pocket in the active site of an enzyme that stabilizes transition state negative charge on a deprotonated oxygen or alkoxide. The pocket typically consists of backbone amides or positively charged residues. Stabilising the t ...

formed with the

backbone The backbone is the vertebral column of a vertebrate. Arts, entertainment, and media Film * ''Backbone'' (1923 film), a 1923 lost silent film starring Alfred Lunt * ''Backbone'' (1975 film), a 1975 Yugoslavian drama directed by Vlatko Gilić ...

amides In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

of Cys163 and Phe400. The

crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric patterns ...

complex with platensimycin employed a C163Q

mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...

, which gave a 50-fold increase in apparent binding. The Gln163

residue Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...

lies adjacent to the

carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...

of platensimycin but makes no specific hydrogen bond. The close proximity of the carboxylate of platensimycin (presumed to be an

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

) to the anionic thiol of Cys163 in the

wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

enzyme may suggest the reason behind the increase in binding of the C163Q mutant. The second set of residues worth considering comprises His303 and His340, which play a role in the decarboxylation mechanism of the malonyl moiety. In particular, His303 activates a structured

water Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...

to attack the carboxylate of the incoming malonyl-ACP.Y M. Zhang, J. Hurlbert, S W. White, C O. Rock, ''J. Biol. Chem.'' 2006, ''281'', 17390-99. The crystal structure of FabF also demonstrates that His340 forms a hydrogen bond between the amide

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

of Leu342 and the N-delta- atom of the

imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-a ...

ring meaning that the lone pair must reside on this atom. In the platensimycin crystal structure the structured water adjacent to His303 is no longer present which may suggest an alternative electronic state for this residue. A strong possibility exists that His303 would present itself as a cation capable of forming an ionic interaction with the benzoic acid group of platensimycin.

References

{{Reflist

External links

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