OSA Newsletter - February 2022

[danaklug]

Dear Friend of Open Source Antibiotics (OSA),

This is our first email update for 2022 (previous one) in which we'll focus on recent progress in both OSA series. If you'd like to get involved and meet the team our next online research meetings will be on Feb 8th for Series 1 (the mur ligases) and Feb 11th for Series 2 (more details on each series Issues page: (Series 1 and Series 2).

Mur Ligase (Series 1)

1. Atomwise update.

Following the wonderful donation from Atomwise of 96 compounds predicted to bind MurE, results from the Diamond soaking experiments have been posted. Seven compounds have been shown to bind to a putative allosteric pocket.

This has been followed up with SPR experiments, and we now need to figure out whether compound binding in this pocket has an inhibitory effect on MurE activity.

2. MurD activity assays.

Elaborated fragments synthesized as part of the round 1 MurD fragment analogues have been tested in a bioactivity assay in order to find dual MurD/MurE inhibitors. Six potential hits were identified (!) and follow-up work has begun. Discovery of a dual mur ligase inhibitor would be a major finding.

3. New crystal structures.
Crystal strucures of P. aeruginosa MurC with two AZ compounds have been published by Dr. Peter Horanyi (Senior Principal Scientist at UCB) and his team. PDB: 6X9N【Pseudomonas aeruginosa MurC with AZ5595】and PDB: 6X9F【Pseudomonas aeruginosa MurC with AZ8074】

A new MurD crystal structure was contributed by Dr. Abendroth Jan (Protein Crystallography Core group leader at Emerald Bio) and his team.
PsaeA.17938.a.B1_7sy9_MurD.pdb

Diarylimidazoles (Series 2)

1. Hypha Discovery and metabolite ID.
We were able to team up with Hypha Discovery to identify a metabolite of OSA_821 using their PolyCYP platform. We were also able to isolate and confirm the structure of this compound, and test for MRSA activity. More information and discussion on this here.

2. Mechanism of action experiments.
Lee Graves's work with multiplex inhibitor beads is ongoing, with results from a HEK293 experiment recently discussed in the Dec. 3 project meeting and posted. Lee is now doing the crucial MoA experiment with MRSA lysate to try to identify a target.

3. Publication draft.
We’ve started drafting the Series 2 publication with updates continuing and journal TBD.

As always:

1. We've 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. We now have a sign-up form for newsletters.

2. Please forward this to anyone you think might be interested. As an open project, everything is in the public domain, and everyone is welcome. Naturally OSA is an excellent place for other people to run their own projects openly.

3. To keep things short, each news email has a limit of three items (well, per series). If you're interested in learning more, then each project has a wiki (Series 1 and Series 2) and an Issue Tracker (Series 1 and Series 2).

Best wishes,

Mat and Dana and all the OSA contributors

(This newsletter may be found online here)

[drc007]

@danaklug @mattodd Would be good to have an actual date for the next meeting in the newsletter.

[mattodd]

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