Dalfopristin is a semi-synthetic

streptogramin Streptogramins are a class of antibiotics. They work as protein synthesis inhibitors. Streptogramin A, Streptogramins are effective in the treatment of Vancomycin-resistant Staphylococcus aureus, vancomycin-resistant ''Staphylococcus aureus'' (V ...

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 ...

analogue of ostreogyrcin A ( virginiamycin M, pristinamycin IIA,

streptogramin A 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: ...

). The combination

quinupristin/dalfopristin Quinupristin/dalfopristin, or quinupristin-dalfopristin, (pronunciation: kwi NYOO pris tin / dal FOE pris tin) (trade name Synercid) is a combination of two antibiotics used to treat infections by staphylococci and by vancomycin-resistant ''Enter ...

(marketed under the trade name

Synercid Quinupristin/dalfopristin, or quinupristin-dalfopristin, (pronunciation: kwi NYOO pris tin / dal FOE pris tin) (trade name Synercid) is a combination of two antibiotics used to treat infections by staphylococci and by vancomycin-resistant '' Ente ...

) was brought to the market by Rhone-Poulenc Rorer Pharmaceuticals in 1999.

(weight-to-weight ratio of 30% quinupristin to 70% dalfopristin) is used to treat

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

s by

staphylococci ''Staphylococcus'', from Ancient Greek σταφυλή (''staphulḗ''), meaning "bunch of grapes", and (''kókkos''), meaning "kernel" or " Kermes", is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillale ...

and by

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...

-resistant ''

Enterococcus faecium ''Enterococcus faecium'' is a Gram-positive, gamma-hemolytic or non-hemolytic bacterium in the genus ''Enterococcus''. It can be commensal (innocuous, coexisting organism) in the gastrointestinal tract of humans and animals, but it may also be ...

''.

Synthesis

Through the

addition Addition (usually signified by the Plus and minus signs#Plus sign, plus symbol, +) is one of the four basic Operation (mathematics), operations of arithmetic, the other three being subtraction, multiplication, and Division (mathematics), divis ...

of diethylaminoethylthiol to the 2-

pyrroline Pyrrolines, also known under the name dihydropyrroles, are three different heterocyclic organic chemical compounds that differ in the position of the double bond. Pyrrolines are formally derived from the aromate pyrrole by hydrogenation. 1-Pyrroli ...

group and

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

of the

sulfate The sulfate or sulphate ion is a polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salts of sulfuric acid and many ...

of ostreogrycin A, a structurally more

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

compound is formed. This

compound contains a readily

ionizable Ionization or ionisation is the process by which an atom or a molecule acquires a negative or positive charge by gaining or losing electrons, often in conjunction with other chemical changes. The resulting electrically charged atom or molecule is ...

group that is available for salt formation.

Large Scale Preparation

Dalfopristin is synthesized from pristinamycine IIa through achieving a stereoselective Michael-type addition of 2-diethylaminoethanethiol on the conjugated double bond of the dehydroproline ring . The first method found was using

sodium periodate Sodium periodate is an inorganic salt, composed of a sodium cation and the periodate anion. It may also be regarded as the sodium salt of periodic acid. Like many periodates, it can exist in two different forms: sodium ''meta''periodate (formula‍ ...

associated with ruthenium dioxide to directly oxidize the sulfur derivative into a

sulfone In organic chemistry, a sulfone is a organosulfur compound containing a sulfonyl () functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of ...

. However, using

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

with

sodium tungstate Sodium tungstate is the inorganic compound with the formula Na2WO4. This white, water-soluble solid is the sodium salt of tungstic acid. It is useful as a source of tungsten for chemical synthesis. It is an intermediate in the conversion of tung ...

in a 2-phase medium produces an improved yield, and is therefore the method of choice for large scale production. The production of the dalfopristin portion of

is achieved through purifying cocrystallization of the quinupristin and dalfopristin from

acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...

solutions.

Physical Characteristics (as mesylate salt)

Antimicrobial activity

Alone, both dalfopristin and quinupristin have modest

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

bacteriostatic A bacteriostatic agent or bacteriostat, abbreviated Bstatic, is a biological or chemical agent that stops bacteria from reproducing, while not necessarily killing them otherwise. Depending on their application, bacteriostatic antibiotics, disinfec ...

activity. However, 8-16 times higher in vitro

bactericidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their p ...

activity is seen against many

gram-positive bacteria 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 ...

when the two streptogramins are combined . While

is effective against

and vancomycin-resistant Enterococcus faecium, in vitro studies have not demonstrated bactericidal activity against all strains and species of common gram-positive bacteria.

Mechanism of action

Both dalfopristin and quinupristin bind to sites located on the 50S subunit of 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 ...

. Initial dalfopristin binding results in a conformational change of the ribosome, allowing for increased binding by quinupristin. A stable drug-ribosome complex is created when the two drugs are used together. This complex inhibits

protein synthesis Protein biosynthesis, or protein synthesis, is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critica ...

through prevention of peptide-chain formation and blocking the extrusion of newly formed peptide chains. In many cases, this leads to bacterial cell death.

Mechanism of resistance

Streptogramin resistance is mediated through enzymatic drug inactivation, efflux or active transport of drug out of the cell, and most commonly, conformational alterations in ribosomal target binding sites. Enzymatic drug inactivation may occur in

staphylococcal ''Staphylococcus'', from Ancient Greek σταφυλή (''staphulḗ''), meaning "bunch of grapes", and (''kókkos''), meaning "kernel" or " Kermes", is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales ...

and enterococcal species through production of dalfopristin-inactivating acetyltransferase or quinupristin-inactivating hydrolase. Efflux or active transport of the drug may occur in coagulase-negative staphylococci and

. Constitutive ribosome modification has been seen in staphylococci with resistance seen in quinupristin only. While resistance to dalfopristin may be conferred via a single point of mutation,

offers the benefit of requiring multiple points of mutation targeting both dalfopristin and quinupristin components to confer drug resistance. Comparatively, only 2-5% of staphylococcal isolates collected in France show resistance to a related streptogramin,

pristinamycin Pristinamycin (INN), also spelled pristinamycine, is an antibiotic used primarily in the treatment of staphylococcal infections, and to a lesser extent streptococcal infections. It is a streptogramin group antibiotic, similar to virginiamycin, ...

, in over 35 years of use.

Drug interactions

Both dalfopristin and quinupristin are extensively hepatically metabolized, excreted from the feces, and serve as an inhibitor of

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

(CYP) 3A4 enzyme pathway. Caution should be taken with concommitent use with drugs metabolized by the

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

pathway. Concomitant use of

with

cyclosporine Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, ecz ...

for 2–5 days has shown to result in a two-fold increase in cyclosporine levels. No adverse effects have been seen in patients with hepatic impairment and no recommendations by the manufacturer have been made for dose reduction of

in this patient population.

Commercialization

While little information is available regarding the regulatory and commercialization history of Dalfopristin alone, Synercid (quinupristin/dalfopristin), made by Rhone-Poulenc Rorer Pharmaceuticals, was approved in 1999 as an IV injectable for the treatment of vancomycin resistant Enterococcus faecium and complicated skin and skin structure infections. Dalfopristin can be purchased alone on the internet from various chemical manufacturers as a

mesylate In organosulfur chemistry, a mesylate is any salt or ester of methanesulfonic acid (). In salts, the mesylate is present as the anion. When modifying the international nonproprietary name of a pharmaceutical substance containing the gr ...

salt.

References

{{reflist Antibiotics Oxazoles Diethylamino compounds