£800,000 grant for optimization of novel antibiotics targeting multidrug-resistant tuberculosis.
Newcastle, UK – September 11, 2019 – Demuris Limited, a company focused on the discovery and optimization of novel, bioactive compounds from natural sources today announced the successful receipt of a grant from the Medical Research Council to fund work at Newcastle University. Demuris is the commercial partner in this grant which will provide £800,000 in funding to investigate the mechanism of action of newly discovered natural product compounds that kill bacteria by inhibiting the RNA polymerase (RNAP) enzyme. As well as paving the way towards new antibiotic drugs, the work supported will provide new insights into the mechanisms of RNA synthesis (transcription).
The collaboration brings together antibiotic production, chemistry, molecular biology and structural biology expertise and is uniquely placed to tackle this problem. Although an important focus will be on fundamental studies of transcription, the anticipated outputs will facilitate the rational design of improved drugs for the treatment of multi-drug resistant Mycobacterium tuberculosis (MDR-TB).
Professor Nikolay Zenkin, from Newcastle University’s Faculty of Medical Sciences and an academic lead of the study, said “This is an exciting development for the future treatment of rifampicin-resistant Tuberculosis and shows what can be achieved when local businesses and universities work together.”
Semi-synthetic rifamycin antibiotics (Rifampicin, Rifabutin) are front line drugs used in the treatment of tuberculosis and target RNAP, but they lose activity in MDR-TB. Demuris, in collaboration with Newcastle University, has discovered a series of novel natural product antibiotics related to a rifamycin analogue called Kanglemycin 1. RNAP is an essential enzyme accomplishing transcription in all living organisms. At the same time, the sequence divergence between bacterial and human RNAPs, makes bacterial RNAP an excellent target for antibiotic development. Understanding the mode of action of RNAP inhibitors at the molecular level has proven to be a powerful research tool in understanding the functions of RNAP itself. Professor Zenkin’s laboratory is a world-leader in the molecular biology of RNAP, and his lab has shown how Kanglemycin retains potent activity even on MDR-TB, facilitating the development of even better antibiotics for treatment of potentially lethal infections.
According to the World Health Organization, Tuberculosis is the leading cause of death by infectious disease, with 10.4 million new cases and 1.7 million deaths annually. Rifampicin-resistance, through the acquisition of mutations in RNAP, is the major problem in the treatment of tuberculosis, with 600,000 new cases reported in 2016. Furthermore, RIF-resistant M. tuberculosis frequently develop multi-drugresistance (MDR-TB) and extensive-drug-resistance (XDR-TB) resulting in 240,000 deaths per year. More worryingly, cases of XDR-TB are emerging which have resistance to second line antibiotics (such as streptomycin, kanamycin, amikacin and fluroquinolones), and the treatment success of these types of 1 Molecular Cell (DOI: https://doi.org/10.1016/j.molcel.2018.08.028) infections is typically <25%. Improved antibiotics active on MDR- and XDR-TB will play a major role in our ability to cope with the huge potential public health impact of Tuberculosis in the future.
About Demuris – Demuris is a spin out company from the University of Newcastle, founded by Prof. Jeff Errington, Director of the University of Newcastle’s Centre for Bacterial Cell Biology – the world’s foremost research centre focused on fundamental studies of bacterial cells.
Demuris has developed proprietary technologies to enhance the discovery and optimization of bioactive compounds from natural sources. This includes its Turbolibrary platform for generating vast numbers of novel, bioactive compounds from previously silent biosynthetic gene clusters. This system is being applied to Demuris’ internal collection of rare taxonomically-sifted actinomycete bacteria obtained from all over the world and from a vast array of diverse environments.
Demuris has also developed a platform of advanced genomics and informatics technologies which enable fast and cost-effective transition from Hit to Drug Lead by rapid dereplication/prioritization of Leads, identification of natural analogues and rapid and efficient compound production.
Demuris is developing lead compounds to address major disease area problems in oncology, mitochondrial disease and drug resistant infectious diseases, with various collaborators and partners.
1 Molecular Cell (DOI: https://doi.org/10.1016/j.molcel.2018.08.028)