A recent paper has caught a lot of attention recently "A Deep Learning Approach to Antibiotic Discovery" DOI from Regina Barzilay's group at MIT. They used a deep neural network model to predict growth inhibition of Escherichia coli using a collection of 2,335 molecules, the molecules were described using Morgan fingerprints, computed using RDKit, for each molecule using a radius of 2 and 2048-bit fingerprint vectors. Using this methodology they identified the known c-Jun N-terminal kinase inhibitor SU3327 which they renamed Halicin. A quick search using MolSeeker allowed identification of the structure and inChiKey.
A search of UniChem using the InChikey NQQBNZBOOHHVQP-UHFFFAOYSA-N identified a number of other identifiers in different databases.
Including a link to the ChEMBL entry CHEMBL510038 giving the biological data 0.7 nM Inhibition of c-Jun N-terminal kinase by time-resolved FRET assay, and links to the original 2009 publication DOI describing the c-JNK SAR. The compound has a rat half-life of 0.45 h. There is another publication that might be of interest describing "Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors" DOI.
Certainly an interesting approach, I suspect the nitrothiazole functionality would set off a few structural alerts but there are certainly of plenty of similar compounds commercially available that would allow exploration of the SAR without too much investment in resources.
What we have: Fragment hits from an initial screen against MurE and MurD, performed at Diamond screening facility, and a platform to screen additional fragment libraries or follow-up compounds.
What we need: Additional chemical matter for screening. The Diamond screening platform is high-throughput and we would ideally be able to take full advantage of this.
Full details are on the Open Source Antibiotics website
I just got news of the first public release of CO-ADD screening data
CO-ADD is a non-for-profit initiative led by academics at The University of Queensland. Our goal is to screen compound for antimicrobial activity for academic research groups and generate a public knowledge database for the development of novel agents for the treatment of microbial infections. The knowledge base contains chemical structures and antimicrobial activity data from CO-ADD’s screening, made publicly available by the academic research groups, with more data to be released over time.
I just thought I’d highlight a new project I’m involved with.
Open Source Antibiotics (https://github.com/opensourceantibiotics) is intended to be a platform for a collaborative effort towards antibiotic discovery.
The first projects have been initiated
Mur Ligase (https://github.com/opensourceantibiotics/murligase) and the background to these exciting targets can be found on the wiki page.
This also provides details of the first two fragment screens.
What we want now is for people to join in and suggest the next round of fragments that should be screened. Ideally these should be commercially available but if people want to design, make and submit their own fragments we would be happy to screen them.
If you feel appropriate, we would appreciate any publicity on this exciting new project
The UK Office of National Statistics has produced a fascinating interactive plot of the causes of death in the UK over the last 100 years.
I've captured a screenshot of the plots but I'd urge to go and have a look at the interactive plot on the website http://visual.ons.gov.uk/causes-of-death-over-100-years/.
What is very apparent is the impact the introduction of antibiotics had in the late 1940's, and the introduction of mass vaccinations, deaths due to infections have been virtually eliminated.
In men heart disease remains the major killer whilst in women it is breast cancer. Sadly among the young it looks like mental health issues are a major concern.
ChEMBL_23 has been released, it was prepared on 1st May 2017 and contains:
- 2,101,843 compound records
- 1,735,442 compounds (of which 1,727,112 have mol files)
- 14,675,320 activities
- 1,302,147 assays
- 11,538 targets
- 67,722 source documents
Data can be downloaded from the ChEMBL ftp site: ftp://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_23
Deposited Data Sets
CO-ADD, The Community for Open Antimicrobial Drug Discovery, is a global open-access screening initiative launched in February 2015 to uncover significant and rich chemical diversity held outside of corporate screening collections. CO-ADD provides unencumbered free antimicrobial screening for any interested academic researcher. CO-ADD has been recognised as a novel approach in the fight against superbugs by the Wellcome Trust, who have provided funding through their Strategic Awards initiative. Open Source Malaria (OSM) is aimed at finding new medicines for malaria using open source drug discovery, where all data and ideas are freely shared, there are no barriers to participation, and no restriction by patents. The initial set of deposited data from the CO-ADD project consists of OSM compounds screened in CO-ADD assays (DOI = 10.6019/CHEMBL3832881).
Modelled on the Malaria Box, the MMV Pathogen Box contains 400 diverse, drug-like molecules active against neglected diseases of interest and is available free of charge (http://www.pathogenbox.org). The Pathogen Box compounds are supplied in 96-well plates, containing 10 uL of a 10mM dimethyl sulfoxide (DMSO) solution of each compound. Upon request, researchers around the world will receive a Pathogen Box of molecules to help catalyse neglected disease drug discovery. In return, researchers are asked to share any data generated in the public domain within 2 years, creating an open and collaborative forum for neglected diseases drug research. The initial set of assay data provided by MMV has now been included in ChEMBL (DOI = 10.6019/CHEMBL3832761).
The World Health Organisation has published a list of the top 12 bacteria for which antibiotics are urgently needed in an effort to focus research.
The list highlights in particular the threat of gram-negative bacteria that are resistant to multiple antibiotics. These bacteria have built-in abilities to find new ways to resist treatment and can pass along genetic material that allows other bacteria to become drug-resistant as well.
Priority 1: CRITICAL
- Acinetobacter baumannii, carbapenem-resistant
- Pseudomonas aeruginosa, carbapenem-resistant
- Enterobacteriaceae, carbapenem-resistant, ESBL-producing
Priority 2: HIGH
- Enterococcus faecium, vancomycin-resistant
- Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
- Helicobacter pylori, clarithromycin-resistant
- Campylobacter spp., fluoroquinolone-resistant
- Salmonellae, fluoroquinolone-resistant
- Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant
Priority 3: MEDIUM
- Streptococcus pneumoniae, penicillin-non-susceptible
- Haemophilus influenzae, ampicillin-resistant
- Shigella spp., fluoroquinolone-resistant
The Community for Open Antibiotic Drug Discovery (CO-ADD) screen compounds for antimicrobial activity for academic research groups for free. The screening includes the top 5 pathogens listed in the WHO priority list, as well as the fungi C. neoformans and C. albicans. Details on how to send compounds are here. All they require is 1mg (or 50uL at 10 mg/mL) of pure compound which will be used for primary screening, hit confirmation, and if active will be used for a broader antimicrobial screening, cytotoxicity and a check for its purity.