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Open Source Antibiotics

Open Source Antibiotics is a consortium of researchers interested in open ways to discover and develop new, inexpensive medicines for bacterial infections.

There are already a couple of projects Mur Ligase and a series of Diarylimidazoles with unknown mechanism. Well worth a read.

All the structures of the molecules on the project are openly available in a spreadsheet https://docs.google.com/spreadsheets/d/168-a1_l51Nfbms67eG8zU8p-EhEtEO26FUzRInbu7fY/edit#gid=2078630269 feel free to have a browse.

New REVIVE Antimicrobial Encyclopaedia

Often when moving into a new therapeutic area it takes a while to pick up all the terms and acronyms, and antimicrobial research has some of it's own, not sure what a MIC is then head over to the REVIVE Antimicrobial Encyclopaedia and search.

The REVIVE Antimicrobial Encyclopaedia includes definitions of terms from the field of antimicrobials including ‘Active Pharmaceutical Ingredient’, ‘Bacterial efflux’ and ‘Minimum Inhibitory Concentration’. Each term has links for users to find more information on the subject and wherever available there are also links to REVIVE content such as webinar recordings and Antimicrobial Viewpoints on the subject. Some terms also include bespoke explanatory videos with clear diagrams featuring REVIVE experts.

REVIVE is a space for everybody with an interest in antimicrobial R&D. The Global Antibiotic Research and Development Partnership (GARDP) is a not-for-profit organization developing new treatments for drug-resistant infections that pose the greatest threat to health. We were created to ensure that everyone who needs antibiotics receives effective and affordable treatment, no matter where they live. We aim to develop five new treatments by 2025 to fight drug-resistant infections, focusing on sexually transmitted infections, sepsis in newborns and infections in hospitalized adults and children.

Open Source Antibiotics

I just thought I'd share this email

Dear Friend of Open Source Antibiotics (OSA),

It's been a busy few months in OSA. Recent activity is being captured in weekly public Zoom meetings (every Friday at 2pm London at https://ucl.zoom.us/j/92800004715), and you can see the details in the recordings of those meetings (like this one) and the associated "Github Issues" (like this one).

Screen Shot 2020-10-21 at 3.33.38 PM

But as part of those discussions we were wondering about the best way to update everyone quickly. While OSA uses Twitter, there is no good substitute for a short email. So this is the first, short OSA news email. Three points:

  1. We have guessed you're interested in receiving occasional emails about OSA. If you're not, just email us back to say you'd like to opt out. Nobody likes spam.
  2. Please forward this to anyone you think might be interested in antibiotics or drug discovery or open science. As an open project, everything is in the public domain, and everyone is welcome.
  3. To keep things short, each news email has a limit of three items. If you're interested in learning more, then each project has a wiki (current project status, like this) and the Issue Tracker (current To Do list and discussion, like this).
So - drumroll - here is the first quick update, focussing on OSA Series 2 (an update on Series 1, the mur ligases, will come soon).
  1. We have confirmed the activity vs MRSA of the diarylimidazoles (exemplar compound OSA821 shown below), originally discovered and explored by Alvaro Lorente and Bill Zuercher at UNC Chapel Hill. A new potency screen is being performed this week at UCL by Paul Stapleton, and includes about 30 compounds that have been donated to the project via Ben Perry (DNDi). This time our potency assay will include a parallel screen of select compounds vs VRE, to see if there is activity vs other high priority Gram +ves.

OSA821

  1. A key aim of the project is to solve the rapid clearance of the known actives. New data from Sue Charman's lab gave clues as to which compounds to investigate next, and we are finalising negotiations for some pro bono work from a UK company towards identification of possible metabolites.
  2. The mechanism of action of these compounds is unknown, but Lee Graves's lab at UNC are in the middle of some MIBs experiments that we hope will reveal, by the end of October, some key new insights into how the compounds work.
Best wishes, Mat and all the OSA Series 2 contributors

OSA logo_low

You can read more about the Open Source Antibiotics on GitHub https://github.com/opensourceantibiotics.

There are currently two projects MurLigase and DiarylImidazoles, everything is in the open and anyone can contribute.

349siteview

Why not swing by and have a browse.

GARDP: Bringing new treatments for drug-resistant infections to all who need them

This webinar provided an overview and update on GARDP’s efforts to bring new antibiotic treatments for drug-resistant infections to all who need them.

The following topics were presented:

  • Antibiotic resistance and the GARDP response
  • Tackling the growing threat of hospital infections
  • Developing new treatments for neonatal sepsis

Discovery of novel antibiotic Halicin using deep learning

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.

halicin

A search of UniChem using the InChikey NQQBNZBOOHHVQP-UHFFFAOYSA-N identified a number of other identifiers in different databases.

halicinUnichem

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.

All code and data is available on GitHub and there is also a website where you can test your own molecules http://chemprop.csail.mit.edu.

chemprop

Call for Open Source Antibiotics Fragment Contributions

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

OSAcallforFrags

Open-access Antimicrobial Screening Database

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.

The database is available here.

COADdatabase

OpenSource Antibiotics

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.

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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.

https://github.com/opensourceantibiotics/murligase/wiki

This also provides details of the first two fragment screens.

MurD https://github.com/opensourceantibiotics/murligase/wiki/MurD-fragment-screen

and

MurE https://github.com/opensourceantibiotics/murligase/wiki/MurE-fragment-screen

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



Causes of death over 100 years

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/.

deaths

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 released

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
Also includes

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).

WHO publishes list of bacteria for which new antibiotics are urgently needed

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.

WHO priority pathogens list for R&D of new antibiotics

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

Update

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.