OSA2 meeting Friday July 31st 2020

[danaklug]

Meeting 31/7/20 at 2pm UK time at https://ucl.zoom.us/j/92800004715. This page follows on from #19.

Recording is here. On the call: me, @danaklug, @edwintse, @drc007

1. UNC team (Carrow Wells) has confirmed required samples are available in fridge. Complete. Need to forward to Monash (Action on Mat).

2. Mechanism of action: Lee Graves at UNC was contacted re relevant experiments (Mechanism of action #15). He asked about the "base cell type" for the experiment. Don't understand this Q. We assume the base cell type is MRSA? Any pointers @TwistedSwisster ? Update: MRSA is the cell type. Need now to start these experiments. Do they need any more compounds? Ask Carrow/Lee (Action on Mat).

3. Monash measurement of in vitro PK. Clearance data - focused array compounds #13 Green light to ship. 3-4 mg each, accurately weighed (though UNC compounds are, it seems, DMSO solutions). The team (Karen White) have sent the necessary customs forms. Mat has thanked the Monash team and will forward requirements to UNC. We have money currently for about 9 in vitro PK evaluations from Monash, plus on final in vivo.

4. MRSA and tox screening for all analogues. Mat has chased Paul Stapleton and Andreas Schatzlein within UCL SoP who have confirmed interest and willingness. There are possible delays owing to emerging from lockdown. Mat has also contacted CO-ADD, who carry out these assays, to see if they are interested. Any other solutions here? Or we proceed? TBD.

5. Synthetic Chemistry. Further to @danaklug's chemistry plan (First round synthesis #16), the chemistry has begun with @edwintse. Update was given in meeting and may be found below (insert link to file on GH then delete this @edwintse @danaklug Action on @edwintse). There was some discussion in the meeting about options for improving yields of specific reactions.

6. Compound numbering for compounds now being synthesised: adopt code system from Molecule Numbering Convention murligase#9 and here that captures batch and salt codes. Update the supersheet with corrected numbers and codes. Done for Series 2 molecules to date. Will probably need to address this also for OSA Series 1 at some point, lower priority. Action on Dana to install note on numbering (e.g. in https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/wiki/Synthetic-Chemistry). Marked as complete.

7. Mat has confirmed the interest from Pfizer in assessing the molecules for metabolic transformation (and isolating the metabolites). These would be pro bono biotransformations on a couple of compounds (they need a couple of mgs per compound). Scott Obach suggested a single methyl at the 2-position of the thiophene could stop clearance if that is where the molecule is being oxidised. He also offered to broker an intro to a UK company, Hypha, which he has now done. Action on Mat to follow up.

8. Is there a rough, high throughput experimental assessment of metabolic liability. What can we use? Preparation of metabolites #7 ? Academic or industrial interest? @danaklug to share search she's done but it doesn't look like there is a "standard in vitro metabolic cocktail". Update - we can't really find anything, so let's stay with in silico. Marked as complete, but can keep Preparation of metabolites #7 open.

9. The similarity landscape: David Drewry (UNC) very kindly put Mat in touch with James Callahan, the corresponding author on the original article reporting these compounds. He's since written. We're setting up a meeting to figure out what GSK might still have and what we can share. Public updates coming as soon as possible.

10. Recurring:
    Design criteria for molecules must keep an eye on logP (use Datawarrior) and predicted clearance (use SMARTCyp, right @drc007 ?). Update: also FAME <-- check. See if we can get hold of it?
    Community updates (standing item, to make sure it's acted upon): We will post weekly meetings like this on Youtube. We need more science update tweets and little videos, using the Tha/Dana protocol (How Can We Democratize Making 30-second Captioned Videos for Updates? OpenSourceMalaria/TechOps#3).

AOB: Target Product Profile work that Dana was doing (#12). Nothing found that was MRSA-specific. Webinar from DNDi was attended by @danaklug and @drc007. Question: single-pathogen projects any use? Sometimes not - clinic likes broad spectrum. These compounds more useful for acute last-resort (<-- expensive trials) infections. What were the CO-ADD results? Dig out to check activity against other bacteria.

Actions (can be checked as complete after the meeting).

• ACTION ITEM: Mat to put UNC and Monash teams in touch to organise sample shipment.
• ACTION ITEM: Decision to be made on where will do the MRSA and tox screening.
• ACTION ITEM: Mat to follow up with Hypha.
• ACTION ITEM: Dana and Ed to post synthetic chem update - perhaps around first week of August @danaklug @edwintse.
• ACTION ITEM: Meeting video to be posted on YouTube.
• ACTION ITEM: Mat/Dana/Ed to meet with GSK team and pursue knowledge of these compounds and any extant samples.
• ACTION ITEM: Dana to install note on compound numbering in synthetic chemistry area of wiki.
• ACTION ITEM: Dig out CO-ADD screening data to check activity vs other bacteria.

[AlvaroLor]

Sorry I’m not able to attend today. I’ll watch the meeting on YouTube when you upload it to see if I can help with anything!

[drc007]

I'll try and attend

[edwintse]

[MFernflower]

@edwintse @danaklug Sorry that I could not attend, but has the workup been the hardest part with regards to your production efforts?

[danaklug]

Re: the point about MRSA-specific activity - Alvaro's compounds were screened at CO-ADD in their primary screen against E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, and S. aureus (MRSA). Of these, S. aureus is the only Gram-positive species; therefore I don't think we can say with confidence that these compounds are MRSA-specific, as they may be active against other Gram-positive bacteria. Something to keep an eye on. Would also be interesting to see if they could be converted to Gram-negative actives (all of WHO's critical priority pathogens are Gram-negative).

[MFernflower]

@danaklug @mattodd Would be nice to get a streptococcus assay

[mattodd]

Closing because moving to #23