Lincosamide derivatives, preparation and use thereof as antimicrobial agents
Dr Jiri Janata, Institute of Microbiology AS CR; Dr Zdenek Kamenik, Institute of Microbiology AS CR; Dr Stanislav Kadlcik, Institute of Microbiology AS CR; Dr Lucie Najmanova, Institute of Microbiology AS CR; Dr Radek Gazak, Institute of Microbiology AS CR
The rising antibiotic resistance has been described by the WHO as one of the biggest threats to global health, food security, and development today. There is a constant call for new-in-class or advanced-in-class antibiotics to treat emerging resistant bacterial infections. Only 15 new antibiotics have been approved in the last two decades, while the antibiotic resistance-related deaths are already estimated at 25 000 per year in Europe alone.
Our patented family of new hybrid lincosamide antibiotics combines features of two naturally occurring molecules. Two lead lincosamide derivatives were developed and partially tested: The first one, ODCELIN, is a hybrid molecule of two natural lincosamides, lincomycin and celesticetin. The second, Cl-ODCELIN, is its chlorinated derivative. The compounds exhibit superior activity against Staphylococcus aureus, Staphylococcus haemolythicus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus fecalis achieving more than ten-fold improvement in activity over standard antibiotics, even against MLS (macrolide-lincosamide-streptogramin) resistant strains. The compounds are also active against Clostridium difficile, overcoming the resistance to clindamycin; 7 of 8 tested resistant strains were sensitive to Cl-ODCELIN, with MICs below 0.25 μg/ml. Advantageously, the compounds can be prepared either by chemical synthesis from the generic drug lincomycin, by enzymatic modification of biosynthesized precursor, or by genetically engineered bacterial strain. The mode of action involves binding to the bacterial ribosome and blocking the proteosynthesis. The details of the MoA and of the resistance profile of our compounds are currently being elucidated. Due to the good tissue (including bone) penetration of our compounds, they are suitable for treating teeth or bone infections. In combination therapy with quinine or quinolones, they can be also be used to treat malaria.
We offer the opportunity to out-license or co-develop the patented lincosamide scaffold. The resulting drug candidates will be able to overcome resistance caused by methylation of a ribosomal target. Possible use of the developed compounds is as general antibiotics, against MRSA and MLS infections or as a malaria treatment. The global bacterial infections market is expected to reach 7.1 B USD in 2026, 1.5 B USD of which is expected to be the MRSA resistant infections. Additionally, C. difficile infections alone are predicted to result in a global market of 1.6 B USD until 2026 and the malaria market size is expected to reach 918 M USD in the same time period.
Technology readiness level (TLR) 3 - 4 (Analytically and Experimentally Demonstrated Proof-of-Concept and Laboratory Validated Component). The antimicrobial activity of the two most promising compounds was tested against a panel of almost 50 microbial strains with variable resistance profiles. The MICs are available for selected strains of S. aureus, S. haemolythicus, S. epidermidis, E. faecium, E. fecalis and C. difficile.
WO2018161979 (A1) (EU and US); CZ307305 (B6), granted 11.04.2018; priority 10.03.2017
S. Kadlcik, Z. Kamenik, D. Vasek, M. Nedved & J. Janata 2017, Chemical science, 8(5), 3349-3355. patentscope.wipo.int/search/de/detail.jsf;jsessionid=91D4450F94A040DF5767474D9B1E110F.wapp2nB