BC-7013 (topical)

[14-O-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin]

Pleuromutilins

Nabriva

Gram-positive

poster……….https://jmilabs.com/data/posters/ICAAC2009/F1-1521.pdf

BC–7013 [14-O-[(3-Hydroxymethyl-phenylsulfanyl)-acetyl]-mutilin] is a novel semi-synthetic pleuromutilin derivative that inhibits prokaryotic protein synthesis.

Pleuromutilins were discovered as natural-product antibiotics in 1950. Tiamulin was the first pleuromutilin compound to be approved for veterinary use in 1979, followed by valnemulin in 1999. It was not until 2007 that retapamulin became the first pleuromutilin approved for use in humans. However, retapamulin is limited to topical application. Recent advances in lead optimization have led to the synthesis of pleuromutilins that combine potent antibacterial activity with favorable pharmaceutical properties, making these compounds suitable for oral and intravenous delivery. Most pleuromutilins have an antibacterial spectrum that spans the common pathogens involved in both skin and respiratory tract infections. Two new pleuromutilins, BC-3205 and BC-7013 (both Nabriva Therapeutics AG), have entered clinical trials. In this review, the key properties of pleuromutilin derivatives, designed primarily through modifications at the C(14) side chain, are presented, and the potential of these compounds in systemic therapy in humans is discussed.

Discovered in 1959, pleuromutilins have the potential to be developed as a new class of antibiotics for systemic use in humans. Although in 2007 retapamulin became the first pleuromutilin approved for topical use in humans, it was not until 2011 that a pleuromutilin antibiotic, BC‑3781, was tested successfully in a Phase 2 clinical trial for systemic use in patients.

BC‑7013 belongs to a series of proprietary Nabriva pleuromutilins, which have been designed by Nabriva’s medicinal chemists to fulfill the specific requirements of a topical antibacterial agent. The clinical study is designed to evaluate safety and tolerability of BC‑7013.

In recent years, bacterial infections resistant to most forms of current antibiotics have appeared throughout the world and are currently the third leading cause of death in the US and Western Europe. Pleuromutilins represent a new class of antibiotics, inhibiting bacterial protein synthesis by binding to unique sites on the 50S subunit of the ribosome. These new antibiotics have two distinct advantages: they have a very low potential for cross-resistance with other established antibacterial classes and display a very low potential for resistance development.

“This is the second pleuromutilin antibiotic Nabriva has moved into clinical trials since our inception 18 months ago, emphasising our view of the potential of this new antibiotic class”, said Rodger Novak, Chief Operating Officer of Nabriva.

Nabriva’s first pleuromutilin program to enter the clinic, BC‑3205, is an oral agent with activity against gram positive and gram negative bacteria and atypicals. BC‑3205 is currently in a multi-dose Phase 1 trial.

Pleuromutilin antibiotics are a novel clinically validated class of antibiotics that specifically inhibit bacterial protein synthesis. Their antibacterial profile covers resistant pathogens, including MRSA, that cause diseases such as respiratory tract and skin infections.

Nabriva Therapeutics’ pleuromutilins are unique antimicrobial compounds that interfere with bacterial protein synthesis via a specific interaction with the 23S rRNA of the 50S bacterial ribosome subunit. These antibacterials have a distinct anti-bacterial profile. Their unique mechanism of action implies a very low probability of cross resistance with other antibacterials. In an industry first, Nabriva’s world class medicinal chemistry expertise achieved the development of intravenous and orally available pleuromutilins clearing the way for i.v. and oral therapy with this antibiotic class. This achievement constitutes a significant milestone in providing appropriate medication for the treatment of life-threatening bacterial infections offering a distinctly different class of antibiotics for the treatment of bacterial diseases.

• New class of antibiotics on the human market
• High target specificity plus a unique mode of action ensures differentiation from existing antibiotic classes and compounds in development
• Very low propensity for resistance development
• Accessibility to both Gram-positive & Gram-negative ribosomes translates into broad spectrum activity against a wide range of infections
• Excellent safety profile
• Oral, intraveneous and topical delivery

Nabriva is the first company with proof of concept achieved for the systemic use of pleuromutilins in patients. Two new pleuromutilins, BC‑3781 and BC‑7013, from Nabriva have shown excellent results in clinical studies. BC‑3781 is about to enter Phase 3. Since Nabriva´s pleuromutilin antibiotics have an ideal anti-bacterial spectrum for both skin and respiratory infections and are available as both oral and i.v. formulations, they address a significant medical need and constitute an excellent commercial opportunity.

mutilins

Mutilin is minor metabolite of the pleuromutilin family, originally isolated from Pleurotus mutilus. Mutilin is formed by hydrolysis of the hydroxyacetyl ester of pleuromutilin, and is a degradation product and in vivo metabolite of

pleuromutilin. Interest in mutilin has focused on its potential as a substrate for generating unique metabolites via
biosynthesis to provide a broader range of targets for semi-synthetic modification.

pleuromutilin

Nabriva. Pleuromutilins. Available online: http://www.nabriva.com/programs/pleuromutilins/ (accessed on 7 December 2012).

Novak, R. Are pleuromutilin antibiotics finally fit for human use? Ann. NY Acad. Sci. 2011, 1241, 71–81, doi:10.1111/j.1749-6632.2011.06219.x.