Thursday, September 29, 2016

Tedizolid Phosphate | Anti-Bacterial | Ribosomal Protein Inhibitors | Treatment of Acute Bacterial Skin and Skin Structure (ABSSS) Infections

Tedizolid phosphate is a novel, second-generation oxazolidinone prodrug which is rapidly converted in vivo by plasma phosphatases to Tedizolid [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one], a synthetic second-generation oxazolidinone antibiotic.

Tedizolid Phosphate

Like Linezolid (first generation oxazolidinone antibiotic) Tedizolid inhibits the synthesis of bacterial proteins by interacting with the 50S subunit of bacterial ribosome, resulting in inhibition of protein synthesis [1].
Tedizolid has been shown to have activity against clinically relevant gram-positive aerobic and anaerobic bacteria, such as Staphylococcus species, Streptococcus species, Enterococcus species, and Haemophilus influenzae.  It has also shown activity against isolates resistant to Vancomycin, Daptomycin, and Linezolid. Tedizolid has nearly equivalent oral and intravenous (IV) bioavailability; therefore, it is developed for oral and IV administration.

Tedizolid: 2D and 3D Structure

Cross-resistance is unlikely, because like a typical oxazolidinone Tedizolid inhibits bacterial protein synthesis by a different mechanism of action from other non-oxazolidinone antibacterial drugs.
Just like Linezolid, Tedizolid behave as Monoamine oxidase inhibitor (MAOI) inhibiting the activity of the monoamine oxidase enzyme family (MAO-A and MAO-B). MAOIs have a long history of use as medications prescribed for the treatment of depression [2].
In early 2013, U.S Food and Drug Administration (US-FDA) designated Tedizolid as a “qualified infectious disease product,” a designation that was created by the Generating Antibiotic Incentives Now (GAIN) Act to provide pharmaceutical companies with incentives to promote the development of antibacterial and antifungal drugs to combat drug-resistant pathogens.
Tedizolid phosphate is an inactive prodrug has few important functions of its own. It enables significantly improved solubility in water and excellent oral bioavailability while also masking the C-5 hydroxymethyl from interactions with monoamine oxidase (MAO). The phosphate group is readily cleaved in blood by serum phosphatase and does not impair antimicrobial potency [2].
Linezolid has also been reported to be associated with peripheral and optic neuropathies, but in a murine model that predicts serotonergic activity, serotonergic effects at doses of Tedizolid up to 30-fold above the human equivalent did not differ from the control group.
On June 20 2014, Tedizolid was approved by the US-FDA as once-day dosage therapy for the treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) [3] caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains, MRSA, and methicillin-susceptible strains), various Streptococcus species (S. pyogenes, S. agalactiae, and S. anginosus group including S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis.

Multidrug-resistant Gram-positive organisms: Concern and Treatment
Multidrug-resistant Gram-positive organisms are commonly causative of nosocomial infections and are associated with significant morbidity and mortality. Some of the most concerning of these pathogens include methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin resistant enterococci (VRE).
Since MRSA was first described in the 1960s, it has become more widespread-first in hospitals and later in the community setting. It still is a major concern as an infection from hospital affecting a large number of patients/people communities. For decades, Vancomycin has been the cornerstone of therapy for invasive MRSA infections. However, recent studies have demonstrated increases in Vancomycin minimum inhibitory concentrations (MICs) for some MRSA strains, including Vancomycin-intermediate and hetero-resistant strains, and reports of clinical failures with Vancomycin have increased [4].
Enterococci are common pathogens in urinary tract infections and endocarditis. Enterococci treatment is a permanent riddle as these pathogens are inherently resistant to most classes of antibiotics, including all commercially available cephalosporins. In addition, enterococci have the ability to develop resistance through mutations and through the transfer of plasmids and transposons from other bacteria. Enterococci remain a common cause of nosocomial infections despite the use of rigorous infection control measures and with Vancomycin no longer a viable therapy in these patients, the search for new and better options in the antimicrobial/antibiotic space is very important.
In April 2000, Linezolid, the first of a new class of antibiotics called oxazolidinones, was approved by the (FDA) for the treatment of serious gram-positive infections, including MRSA, VRE, and Streptococcus pneumoniae. Though Linezolid is blessed with features such unique mechanism of action, the availability of i.v. and oral formulations, and its potent in vitro activity but the problems soon arised. The limitations of Linezolid include the need for twice-daily dosing, drug interaction potential (with serotonergic agents), and concern for bone marrow suppression with prolonged therapy. In addition, reports of Linezolid-resistant strains of S. aureus and enterococci were reported shortly after it became available on the market.
Tedizolid is the developed to overcome the failures of Linezolid. It is once-a-day pill and is also effective against Linezolid-resistant strains. Tedizolid is designed on Linezolid template using a rational drug design algorithm where new functional groups are added in manner that side-effects from Linezolid are minimized.

Tedizolid: Spectrum of Bactericidal Activity and Mechanism of Action
Tedizolid is active against gram positive organisms, including staphylococci, streptococci, enterococci, and certain anaerobes. In comparison with Linezolid, Tedizolid has been shown to have 4- to 16-fold greater in vitro activity against methicillin-sensitive S. aureus, MRSA, streptococci, and enterococci. Tedizolid also has activity against some gram-negative pathogens [4, 5].
Several in vitro studies also demonstrated the activity of Tedizolid against Linezolid resistant bacteria especially S. aureus with the chloramphenicol-florfenicol resistance (cfr) gene. Organisms resistant to oxazolidinones via mutations in genes encoding 23S ribosomal RNA or ribosomal proteins (L3 and L4) are generally cross-resistant to Tedizolid.
Mechanism: The mechanism of action of Tedizolid just like its predecessor Linezolid is through inhibition of protein synthesis. Tedizolid inhibits the translation process of bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit and preventing the formation of the 70S initiation complex.
Tedizolid also has additional interactions with the peptidyl transferase binding site region of 23S rRNA, which is believed to contribute to its lower minimum inhibitory concentration (MIC) values compared with Linezolid [1,2].

Dosages and Approvals:
Tedizolid phosphate (Tradename: Sivextro) is developed and launched by Cubist Pharmaceuticals (a subsidiary of Merck) following acquisition of Trius Therapeutics. The originator of Tedizolid is Dong-A Pharmaceuticals. In 2007, Trius Therapeutics announced that they have entered into a license agreement with Dong-A pharma on a novel series of oxazolidinone-class antibacterial compounds. Under the agreement, Trius has acquired exclusive worldwide rights, outside of Korea, to develop, manufacture and market these agents. Trius initiated Phase I trials with the lead compound, Tedizolid (also known as TR-701, DA-7218).
Tedizolid is available as a 200 mg tablet and as a vial containing 200 mg lyophilized powder for injection. The recommended dose is one 200 mg tablet orally taken with or without food or one 200 mg IV infusion daily for six days for the treatment of SSTIs in patients 18 years of age and older. The 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted in 250 ml of normal saline. After reconstitution and dilution, Tedizolid should be infused over one hour. Tedizolid is incompatible with solutions containing divalent cations, including Lactated Ringer’s and Hartmann’s Solution. Advanced age, hepatic impairment, and/or renal impairment do not necessitate a dosage adjustment [3].

Reported Activities for Tedizolid:
A summary of various activities reported for Tedizolid in scientific literature. The important bactericidal activities are [6]:
Gram-positive bacteria      
          MIC90(Inhibition of Corynebacterium jeikeium Activity) = 0.5 ug/ml
          MIC90(Inhibition of Listeria monocytogenes Activity) = 0.25 ug/ml
Staphylococcus species  
          MIC90(Inhibition of S. aureus  (MS) Activity) = 0.25-0.50 ug/ml
          MIC90(Inhibition of S. aureus  (MR) Activity) = 0.25-1.0 ug/ml
          MIC90(Inhibition of Coagulase-negative staphylococci  (MS) Activity) = 0.5 ug/ml
          MIC90(Inhibition of Coagulase-negative staphylococci  (MR) Activity) = 0.5 ug/ml
Streptococcus species     
          MIC90(Inhibition of S. pneumoniae Activity) = 0.25 ug/ml
          MIC90(Inhibition of S. pneumoniae  (PI and PR) Activity) = 0.25-0.50 ug/ml
          MIC90(Inhibition of S. agalactiae Activity) = 0.25-0.50 ug/ml
          MIC90(Inhibition of S. pyogenes Activity) = 0.25-0.50 ug/ml
          MIC90(Inhibition of Viridans group Activity) = 0.25 ug/ml
Enterococcus species      
          MIC90(Inhibition of E. faecalis  (VS and VR) Activity) = 0.50-1.0 ug/ml
          MIC90(Inhibition of E. faecium  (VS) Activity) = 0.50-1.0 ug/ml
          MIC90(Inhibition of E. faecium  (VR) Activity) = 0.5 ug/ml
Gram-negative bacteria    
          MIC90(Inhibition of Haemophilus influenzae Activity) = 16 ug/ml
          MIC90(Inhibition of Moraxella catarrhalis Activity) = 4 ug/ml
          MIC90(Inhibition of Bacteroides fragilis group Activity) = 4 ug/ml
          MIC90(Inhibition of Clostridium perfringes Activity) = 2 ug/ml
          MIC90(Inhibition of Peptostreptococcus species Activity) = 0.5 ug/ml
          MIC90(Inhibition of Prevotella species Activity) = 4 ug/ml

Other Activities for Tedizolid
IC50 (Inhibition of MAO-A Activity) = 8.7 uM
IC50 (Inhibition of MAO-B Activity) = 5.7 uM
IC50 (Inhibition of Mitochondrial Protein Synthesis (MPS) Activity) = 0.3 uM

Common name: DA-70157; DA-70218; DA-7157; DA-7218; TR-700; TR-701; TR-701 FA; TR-701 free acid; Tedizolid phosphate; Torezolid; Torezolid phosphate; BAY 1192631; Tedizolid
Trademarks: Sivextro
Molecular Formula: C17H15FN6O3 {C17H16FN6O6P}
CAS Registry Number: 856866-72-3 {856867-55-5}
CAS Name: (R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one {(R)-(3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl dihydrogen phosphate}
Molecular Weight: 396.38 {450.32}
SMILES:OC[C@H](OC1=O)CN1C(C=C2)=CC(F)=C2C3=CN=C(C4=NN(C)N=N4)C=C3 { O=P(O)(O)OC[C@H](OC1=O)CN1C(C=C2)=CC(F)=C2C3=CN=C(C4=NN(C)N=N4)C=C3}
InChI: InChI=1S/C17H15FN6O3/c1-23-21-16(20-22-23)15-5-2-10(7-19-15)13-4-3-11(6-14(13)18)24-8-12(9-25)27-17(24)26/h2-7,12,25H,8-9H2,1H3/t12-/m1/s1 { InChI=1S/C17H16FN6O6P/c1-23-21-16(20-22-23)15-5-2-10(7-19-15)13-4-3-11(6-14(13)18)24-8-12(30-17(24)25)9-29-31(26,27)28/h2-7,12H,8-9H2,1H3,(H2,26,27,28)/t12-/m1/s1}
Mechanism of Action: Ribosomal Protein Inhibitors; Monoamine Oxidase Inhibitors; Serotonin Modulators
Activity: Treatment of Acute Bacterial Skin and Skin Structure (ABSSSI) Infections; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics
Status: Launched 2016 (US)
Chemical Class: Small molecules; Oxazolidinones; Flourine containing; Tetrazoles; Organic phosphoric acids
Originator: Dong-A Pharmaceuticals/ Cubist Pharmaceuticals

*Data in { } bracket is for Tedizolid phosphate.
1 2 3