Step forward for synthesis of complex peptides
The antibiotic belongs to the lantibiotics class, which were discovered 80 years ago but their use has been hindered by the lack of a cost-effective method of producing sufficient quantities.
Differentially Protected Orthogonal Lantionine Technology (DPOLT) has now overcome this problem to produce a synthetic analogue of MU1140, ONI’s lead antibiotic candidate.
Dr Jeffrey Hillman, ONI's chief scientific officer, said: "This successful proof of principle of DPOLT is the result of many years of very hard, extremely imaginative work by our scientists.
“In addition to MU1140, this technology will allow us to synthesise all 50 of the known lantibiotics and to conveniently modify their structures in order to improve their usefulness as antibiotics for the treatment of infectious diseases. In effect, DPOLT should provide a much needed pipeline of antibiotics at a time when drug resistant bacteria are on the rise."
The commonly used solid phase peptide synthesis (SPPS) technology is not an efficient system for producing some complex proteins. This limitation has restricted the production of lantibiotics, many of which consist of intertwined rings.
DPOLT builds upon the SPPS system but uses two unusual amino acids with protecting groups on their reactive carboxyl and amino groups, which can be removed as needed.
This allows for DPOLT to be integrated into existing SPPS systems, with the modifications making the platform capable of quickly and cost effectively synthesising pure lantibiotics.
Further development of the technology is now underway, with ONI retaining the services of Almac Sciences to assist with this.
Almac’s contract manufacturing division will be working on refining and scaling-up production of the MU1140 analogue, with the goal of producing sufficient quantities for regulatory approval.
ONI believes MU11440 could be effective in the treatment of infections by MRSA and other drug resistant Gram positive bacteria, which have been major political topics in some countries in recent years.
Figures from the Health Protection Agency (HPA) for the 2007 financial year recorded 45,334 cases of Clostridium difficile and 4,448 cases of MRSA in UK hospitals.
In addition, preliminary studies suggest that MU11440 could be the first new antibiotic to be developed in 35 years for the treatment of tuberculosis.
Beyond MU11440 there is the possibility of synthesising more lantibiotics, the prospect of which led Stanley Stein, ONI’s CEO, to describe the development of DPOLT as “a seminal healthcare event”.
