Demuris has secured a £342,160 grant from Innovate UK to continue the development of a novel class of antibiotics for the treatment of multi-drug resistant Mycobacterium tuberculosis (MDR-TB).
Demuris, in collaboration with Newcastle University, has discovered a series of novel natural product antibiotics related to a rifamycin analogue called Kanglemycin1. Semi-synthetic rifamycin antibiotics (rifampicin, rifabutin) are front line drugs used in the treatment of TB and target RNA polymerase (RNAP) – an essential enzyme for transcription in all living organisms.
Crucially, Demuris’ analogues are active against rifampicin-resistant MDR-TB so that they have the potential to replace rifampicin as front line anti-TB drugs. This grant will allow the company to create semi-synthetic derivatives of the Kanglemycin series using rational drug design and the testing of these compounds in a TB disease model.
According to the World Health Organization, in 2016 there were around 600,000 new cases of rifampicin-resistant TB, which resulted in around 240,000 deaths. Based on global surveillance of resistance, 4.1% of new and 19% of previously treated TB cases are estimated to be rifampicin or multidrug-resistant (RR-/MDR-TB).
More worryingly, cases of extensively drug-resistant TB (XDR-TB) are emerging which have resistance to first and also second line antibiotics (such as streptomycin, kanamycin, amikacin and fluroquinolones), and the treatment success of these types of infections is typically <25%.
This grant will allow Demuris to create a series of semi-synthetic compounds and enable detailed ADMET testing of the compounds, followed by efficacy studies in a TB disease model. It is projected that this work will allow the identification of a preclinical candidate with potential application in the treatment of MDR-TB.
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 the 3G 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 in partnership with various collaborators and partners.
1Molecular Cell (DOI: https://doi.org/10.1016/j.molcel.2018.08.028)