Mycetoma Monthly Meeting 23 August 2022

[fantasy121]

Time 23rd Aug 2022 GMT 20:00 (Sydney +1 day 6 AM, London 9PM, Amsterdam 10PM, New York 4PM) check your calendar invites

Chair UCL Minute taker: USYD --> minutes were taken by ErasmusMC

Recording here

Minutes: Admin

• [ ] @fantasy121 missed the meeting since he had to wake up very early. For most other team members it was relatively late. We moved the time from June also to the Europe midday scheme. Is the rotating scedule still prefered by everyone or should we make another time schedule for our monthly meetings? Let's make this an agenda item this during the next MycetOS meeting.
• [ ] We discussed that it is not convenient that the current zoom link is created by the university of Sydney. This means that we cannot record the meeting when they are not present. For that a backup meeting address is needed, or a link with the conditions that everyone can be host. @wwjvdsande commented that her department has no zoom account only teams. @dmitrij176 commented that their department has both zoom and teams. Both @dmitrij176 and @wwjvdsande will look up if these links can be made in such a way that everyone joining can be made host.
• [ ] -

List of epichem compounds to address the SAR gap_

• [ ] Hung has made his list of potential compounds for gap, @dmitrij176 indicated that he still is to go through the epichem library to find compounds for SAR gap. When both @fantasy121 and @dmitrij176 have made their lists they need to be compared and ordered via Martine to ship the compounds in one shipment.

Missing SMILES strings_ (Dmitrij compounds and Breaking Good compounds (Kym). Needs to update SMILES then ask Ben to generate LogD values.

• [x] @dmitrij176 promised to add the missing SMILES stings
• [x] could @fantasy121 or @kym834 do the same for the Breaking Good compounds?
• [ ] when the smiles are added @wwjvdsande will ask @bendndi to calculate the LogD of these compounds

*Series 1 Manuscript Draft**_ Hung has updated chemical data and SAR onto the draft. Hung also updated chemical data on the in vivo document.

• [ ] Mat and Wendy will review the draft @mattodd @wwjvdsande
• [x] Hung will ask Alice/Peter to review the draft (co-authoring) @fantasy121
• [x] @wwjvdsande will grant Alice and Peter access to the dropbox file

Screening compound series in vitro

• [x] @mmos screened the natural compounds and the newly synthesized compounds against Madurella mycetomatis in vitro The data will be uploaded in the spreadsheet. Again for some of these compounds the smiles are not present yet. Of the compounds tested there was one fenarimol analogue of @dmitrij176 which was active and several of the compounds from @AndreaOtago. The natural compounds often reacted with the plastic of the 96 well plate. They were diluted further for screening purposes. The natural compounds were tested in %v/v they will be recalculated to uM.
• [x] @MA-Jjingyi screened compounds from series 1 and series 6 _in _vivo as well as some of the natural products__ So far only one fenarimol did significantly prolong larval survival. No activity was seen in the others tested. Also no activity was seen in the ketoxomines. When the triplicate data is available the survival data will also be added in the spreadsheet

Agenda:

Action Items

Admin

• [ ] We need to generate backup meeting links for recording purposes as Zoom accounts only allow co-host privilege to people of the same organisation. UCL and/or Erasmus to create alternative Zoom/team links to host, in case main link cannot be used for recording. (@dmitrij176 @mattodd @MA-Jjingyi @wwjvdsande)

List of epichem compounds to address the SAR gap

• [ ] Hung has made his list of potential compounds for gap

• [ ] Dmitrij to independently look through the epichem library to find compounds for SAR gap. (@dmitrij176) We will merge the two list together, then ask Martine to ship the compounds in one shipment.

Missing SMILES strings (Dmitrij compounds and Breaking Good compounds (Kym). Needs to update SMILES then ask Ben to generate LogD values.

• [x] Dmitrij compounds @dmitrij176
• [x] Breaking Good compounds @kym834

Series 1 Manuscript Draft Hung has updated chemical data and SAR onto the draft. Hung also updated chemical data on the in vivo document.

• [ ] Mat and Wendy will review the draft @mattodd @wwjvdsande
• [x] Hung will ask Alice/Peter to review the draft (co-authoring) @fantasy121

RACI2022 Hung shared his experience at RACI 2022 conference. Fenarimols Series 1 work was presented at this conference. Rohan Davis (Mat’s OSM collaborator @mattodd) was interested in sending some anti-malarial compounds from his lab in Griffith University for mycetoma testing. (need to post structures)

• [ ] Hung to contact Rohan for follow-up @fantasy121

• [ ] Hung to Ask Alice and Peter for Funding opportunities to continue screening. @fantasy121

Series 2 and other series

• [x] @kym834 to update on series 2 work with SSP and high school students and double check there is no doubling of compounds synthesis from different participating high schools (Australia vs Seven Oaks for eg).

• [ ] AndreaOtago has sent 17 compounds which are currently prepared for screening csuth22 will sent additional compounds as well. Codes need to be assigned to these compounds and the Master List needs to be updated. Can we please have a volunteer?

Updates:

• USYD
• UCL
• Erasmus

AOB

[mattodd]

Hi all - sorry again to have to miss the last meeting. Thanks for starting this issue in lots of time, @fantasy121.

A request re minutes - can we please put minutes text into the main body of an Issue, rather than in a separate Word file? It means that we can more easily find things using Github's search function and browse text. So, minutes/actions/developments should be folded into the Issue of a particular meeting.

I was listening to a talk today from Mark Blaskovich from CO-ADD. They have published a preprint summary of some metal complexes that they have screened as antifungals, including in a G. mellonella infection model. @wwjvdsande shall I reach out and see whether we can get samples of the actives?

[bebi78]

@mattodd Seems that the most promising compound is the COD-platinum complex Pt1, which is a common starting material in platinum chemistry. It is important to know how the complex was applied, since DMSO is not an inert solvent for platinum complexes.

[bebi78]

@fantasy121 I prepared some metal complexes from commercially available antifungal imidazoles such as clotrimazol recently, for an antiparasitic drug discovery project. Might be also applicable for some of your compounds. Such complexes probably won't coordinate the cytochrome iron anymore, but in case they are active they would provide a hint at alternative mechanisms of action.

[MFernflower]

@mattodd @bebi78 @wwjvdsande is series 7 our natural product and analogue foray? - Might need to change repo information

[mattodd]

@MFernflower we've an existing repo to capture screening of "adjuvants". I think we designate a series number when we get specific and start exploring structures. For random screening discussions we also have this.

[MFernflower]

@mattodd alright I'm not going to rename anything - sorry I could not attend yesterday's meeting

On Wed, Jul 27, 2022, 3:45 AM Mat Todd @.***> wrote:

@MFernflower https://github.com/MFernflower we've an existing repo https://github.com/OpenSourceMycetoma/Adjuvant-Screen to capture screening of "adjuvants". I think we designate a series number when we get specific and start exploring structures. For random screening discussions we also have this https://github.com/OpenSourceMycetoma/What-other-molecules-to-screen.

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/79#issuecomment-1196377970, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDWTHL4TRMT6SA25NODVWDSKNANCNFSM54VXEYHA . You are receiving this because you were mentioned.Message ID: @.***>

[bebi78]

@MFernflower See video of the meeting for explanation of series 7. I think Wendy has labelled them so. @mattodd Our metal PhD student told me we have still some mg of the COD platinum complex Pt1 I can share. Would be nice if Dr. Blaskovich or some of his coauthors like the godfather of metal-based drugs Peter Sadler could join on github.

[wwjvdsande]

@mattodd @bebi78 this sound OK to me. I will be away for a few weeks but you can contact @MA-Jjingyi in case anything needs to be arranged.

[MFernflower]

@wwjvdsande @bebi78 with regards to chlorpromazine and the series 3 - it seems like it was screened as part of a MMV box but it seems a bunch of data is missing from the sheet about it? - so maybe re screen material provided by @bebi78 is useful?

@bebi78 if you have trifluoperazine as well to send with the chlorpromazine that could be useful as that's a known fungal calmodulin inhibitor

[bebi78]

@MFernflower Sorry, I don't have trifluoperazine. But today I received buparvaquone. So next week I will send @wwjvdsande and @MA-Jjingyi chlorpromazine, buparvaquone, and COD-PtCl2.

[wwjvdsande]

@OpenSourceMycetoma/corecontrib we are currently in the meeting, however there is just the three of us. Is someone else joining

[MMos2022]

@fantasy121 Hello, I am trying to join the meeting but am struggling to find a link for it. Thank you

[wwjvdsande]

@fantasy121 we used the link in the outlook invite https://uni-sydney.zoom.us/j/99281549497

[wwjvdsande]

@fantasy121 we will start

[mattodd]

Apologies, I'd thought the meeting was an hour later. Will catch up with actions later on. Let me know if it's time for me to look at the paper again, and how the SI is looking.

On Tue, 23 Aug 2022, 21:06 Wendy van de Sande, @.***> wrote:

@fantasy121 https://github.com/fantasy121 we used the link in the outlook invite https://uni-sydney.zoom.us/j/99281549497

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/79#issuecomment-1224779581, or unsubscribe https://github.com/notifications/unsubscribe-auth/ABBO2NOXKEMBIEWEM7PPY3LV2UVLZANCNFSM54VXEYHA . You are receiving this because you were mentioned.Message ID: @.***>

[fantasy121]

Hi team, apologies I accidentally slept through the meeting time as I got the wrong alarm on 😅.

@mattodd @wwjvdsande Re: paper writing. Peter has reviewed the draft on my end and put it some edit suggests. He has also volunteered to make some more edits in the actual draft (he was having some issues with access earlier but I'll sort this out).

He asked me to forward this to the team: "If we need somebody to tidy this draft up/ incorporate the various changes and edits flagged in this draft, I am happy to volunteer for that task if you would like, and would be able to do this over the next couple of weeks."

@OpenSourceMycetoma/corecontrib Peter will start this process once everyone is happy for him to do this. Just let me know and I'll let him know.

[bebi78]

@wwjvdsande What would be the next step after the larvae tests, tests in mice? I'm asking because Pterohepam was published last year by a Chinese group in J Med Chem and showed no toxicity to mice at high doses in their paper. But it was shown to be toxic to larvae here. Because mice are a mammalian model closer to humans than larvae, I wonder if Pterohepam can reach more advanced stages of antifungal testing. @MMos2022 Can you upload your presentation from last week?

[wwjvdsande]

@bebi78, mice would be a next step before clinical evaluation. However for mouse experiments I really need to acquire funding and a very strong case to get the approval from the ethical committee. The laws in the Netherlands are very strict for animal experiments and mouse experiments are way more costly than larval ones. Larvae are invertebrates and they are not included in that same law. Due to the toxicity we demonstrated in the larvae, additional toxicity test would be necessary to be able to test it even in mice. Might be more pragmatic to keep the mouse model for the compounds in which we demonstrated very good activity in the larvae.

[bebi78]

@wwjvdsande Did not know that you have the facilities to do mouse tests. I expected this to be done be DNDi partners. We are using chicken (CAM assay) and zebrafish embryos as surrogates which don't fall under the ethics law, either. Maybe the CAM assay might be an alternative for larvae tests over the winter season. Pterohepam was given ip at doses of 30 mg/kg every four days without causing weight loss in the treated mice (see link to the paper). It has a combined HDAC inhibitory and immune modulatory effect (STAT3 inhibition). https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00136 I'm eager to know the activities of the naphthoquinones such as plumbagin from the blue box, and of the solids from the orange box such as magnolol and honokiol, that's why I was asking for uploading Mimi's presentation. Could not find data about it in the excel sheet.

[bebi78]

@wwjvdsande @MMos2022 Thanks for adding the results to the biological data excel file. Question: The activities of the perfumes/liquids are all presented in 1/0.25% concentrations, and the solids in 100/25 µM concentrations?

[fantasy121]

@wwjvdsande Could you add Peter to the Dropbox folder with the shared draft manuscript so he can do edit/reviews thanks. I emailed you his contact.

[bebi78]

Meeting tomorrow?

[mattodd]

Yes, we're meeting, but we need a new Issue set up and the above action items digested a little. @OpenSourceMycetoma/corecontrib would someone like to set this Issue up? I confess I'm not sure whose turn it is.

[dmitrij176]

Good evening. According to roster 2022 #52, USYD is scheduled to host MycetOS September meeting. I have set up the new issue #80, but the new meeting time has not been decided (mentioned in August minutes). Due to time zone differences, most participants will probably miss the meeting because of late notification. I suggest that we postpone the meeting by at least one day to allow everyone to prepare and make it on time. It depends on what the new meeting time will be. @mattodd @wwjvdsande @bebi78 @ can we please decide what date/time would be most convenient for us?

[mattodd]

Meeting is in my diary for 12 noon UK time Tuesday, which is 1pm EU time and 9pm Sydney. If that tallies with our expectations, then we can go ahead.

[dmitrij176]

I dont have the new meeting schedule. The question is will other MycetOS members will be able to join? Usually, meeting time is known in advance.

[wwjvdsande]

@OpenSourceMycetoma/corecontrib we also were working with the time of today so both me and @MA-Jjingyi are prepared for today. If I recall from the last meeting we still needed to decide on the new meeting time and that was one of the subjects from todays meeting

[fantasy121]

Meeting is in my diary for 12 noon UK time Tuesday, which is 1pm EU time and 9pm Sydney. If that tallies with our expectations, then we can go ahead.

I have this time for my calendar invite. And will be able to make it Thanks.