MycetOS 2020 Meetings — Actionable Items

[fantasy121]

Here you will find actionable items from all past Open Source Mycetoma Meetings. To be updated by all members once their designated tasks are completed.

• [ ] ACTION ITEM: Dmitrij @dmitrij176 to add his experimental data to this google doc once he has finished writing it all up. Almost done.

• [ ] ACTION ITEM: Hung @fantasy121 and Dmitrij @dmitrij176 to start working on writing up the results for the synthesis. Wendy and Co. to do the same for the in vitro studies.

• [x] ACTION ITEM: Matt has asked that everyone check that any molecules you have made are on this list. A new issue thread to be created only for people to share the compounds they are working on and to be updated as work progresses. Ben to add the new ones shared on the new thread to his list. DONE

• [x] ACTION ITEM: COVID moonshot project has a nice way of doing this that might work for us. Ben @bendndi to find out more about this and report back at the next meeting.

• [ ] ACTION ITEM: Matt @mattodd had a student who did some work on molecular weight and size on grain penetration. Matt to share this work and data once able to.

• [ ] ACTION ITEM: Manuscript underway, intro, material, methods almost done. Wilson @wilson-Lm will add onto GitHub.

• [x] ACTION ITEM: Hung to create Open Source Mycetoma and upload meetings on there. DONE

• [x] ACTION ITEM: Anthony/MFernflower – start new GitHub issue with information on the compounds we need to send over for amoeba testing. [DONE] (https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/30)

• [x] ACTION ITEM: Hung – Check inventory for 2 active and 2 inactive compounds, do you have enough for the amoeba screen? Yes

• [x] ACTION ITEM: Hung @fantasy121 - Verify NMR's of the four compounds and then send them over to @MOUSEY007 for the PFLA screen.

• [x] ACTION ITEM: Chris @MOUSEY007 to perform screening and intro for the PFLA screen. (final screening data should be available in a few more weeks)

[bendndi]

I've been discussing with the PostEra team to see if there is some interest in them sharing the tools they have developed for COVID moonshot to the open source pharma community in a more general sense. I've suggested some additional functionality they could add in to make it even more appropriate for OSN-type activities (right now COVID moonshot is great at tracking suggested designs but not so good for tracking and assigning synthesis efforts - I've suggested a way that could allow both). I'll update at next meeting.

[mattodd]

Probably easier to do that last step by email, if one of you @fantasy121 @MFernflower would like to reach out that way? Some people don't want to share names and addresses publicly, and for many courier services a phone number is required.

[Wilson-Lm]

Hi, a link to the manuscript has already been posted on the other page. I'll post it on here again. Ive shared it via google docs. and anyone with access to this link is able to edit and give comments

Manuscript link: https://docs.google.com/document/d/13iRAEGrZfuupZUADGE5y_iJuicfP5jI0eFRFbVPGOLc/edit?usp=sharing

[MFernflower]

@fantasy121 Regarding the ameba screen: Contact christopher.rice@uga.edu to exchange shipping info - ignore posts on twitter since they are now outdated!!!

[MFernflower]

@mattodd @MOUSEY007 confirmed shipment from Hung so I check off the box

[MOUSEY007]

Dear all,

After an intense battle (8 emails, 2 forms and 2 phone calls) with customs, we now have the 4 compounds for screening. They arrived this afternoon EST. They are now in my pipeline and Balamuthia should be ready for screening in 2 week (slow grower). I'll be back in touch once I obtain 2 biological replicates of screening data.

Regards Chris

[MFernflower]

@MOUSEY007 @wwjvdsande @Wilson-Lm I just looked over what MMV has put in the coronavirus box - some compounds are rather interesting - some perhaps screen worthy for mycetoma and PFLA infection!!!!

[MOUSEY007]

I believe we’ve already screened all the compounds in that box through independent screening.

[MFernflower]

@MOUSEY007 the box includes a few compounds that would not be covered by the FDA approved library so it's theoretically possible something pre-clinical could kill PFLA's or mycetoma

[wwjvdsande]

@MFernflower, we received a copy of the box. We will start screening in the upcoming month.

[MFernflower]

@MOUSEY007 Dr.Rice is all going well?

[MOUSEY007]

Analysing the data now and the second repeat for Acanthamoeba doesn't look good. I will have to repeat this next week and analyse the following week. I'll post the Balamuthia and Naegleria data soon.

[MOUSEY007]

Open Source DD summary.xlsx

Here is the data so far, this is what happens when I rush :( I'll set up a repeat for Acanthamoeba and Naegleria, over the next two weeks, since it looks like some of the compounds didn't perform as we obtained the first time. I will make this from fresh stocks as I tried to freeze thaw these plates and have had issues in the past with azoles freeze thawing. The Bm data looks consistent.

[MOUSEY007]

Dear all, Here is the final results from the screen in the last tab named table. For our drug discovery screening program we are looking for drugs that are <1 uM activity to move forward with. As none of these had that level of activity, I do not see the worth in doing follow up and more expensive assays for secondary prioritisation studies for these molecules. Happy to discuss this project if these may lead to other SAR or chemical inference. I have a meeting with Dr. Kyle on Friday and can give an update of what we discuss. Hope you are all keeping well and safe! Chris Open Source DD summary.xlsx

[MFernflower]

@MOUSEY007 Dr.Rice I once again thank you for screening these compounds - It seems like our molecules are pretty well targeted to eumycetoma - unlike the Posaconazole or Ketoconazole that is currently used to treat both Naegleria infections and eumycetoma alike.

@mattodd @fantasy121 This is important information (screens vs other organisms) to have in a paper - I will upload data to github

@Wilson-Lm @wwjvdsande Do you have the ability to screen against other pathogenic fungi other than eumycetoma?

Pseudallescheria boydii? Aspergillus? Mucormycosis?

Would be interesting to see how narrow spectrum our drugs are!!

[wwjvdsande]

@MFernflower @mattodd @fantasy121 It is good to know. We have a panel of other fungal mycetoma causative agents which we should screen as well. I have a new student beginning by the end of october and that will be a good project for her. On top of that we also have a collection of Aspergillus species and Candida species. The Aspergillus species I worked with myself so I can locate that quite easily. I will look for the Candida pannel as well. We also have a diagnostic department here. I will ask them to keep any azole resistant isolates for us as well. Might be good to screen against those as well. Since the fenarimols are thought to have the same antifungal target as the azoles would be good to determine if there is cross-resistance as well.

[MFernflower]

There are other ascomycete genera that cause mycetoma? @wwjvdsande https://github.com/wwjvdsande you have piqued my interest and I am now wondering if you have a list you could share with me!

On Thu, Sep 24, 2020, 2:10 AM Wendy van de Sande notifications@github.com wrote:

@MFernflower https://github.com/MFernflower @mattodd https://github.com/mattodd @fantasy121 https://github.com/fantasy121 It is good to know. We have a panel of other fungal mycetoma causative agents which we should screen as well. I have a new student beginning by the end of october and that will be a good project for her. On top of that we also have a collection of Aspergillus species and Candida species. The Aspergillus species I worked with myself so I can locate that quite easily. I will look for the Candida pannel as well. We also have a diagnostic department here. I will ask them to keep any azole resistant isolates for us as well. Might be good to screen against those as well. Since the fenarimols are thought to have the same antifungal target as the azoles would be good to determine if there is cross-resistance as well.

— You are receiving this because you were mentioned. Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/31#issuecomment-698135339, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDSLXOG7HDHFRUMHBETSHLPGNANCNFSM4ORQCDVA .

[wwjvdsande]

@MFernflower. Mycetoma can actually be caused by more than 70 different micro-organisms, both fungi and bacteria. The fungi all belong to the phylum ascomycota. The majority of the causative agents are either sordariales or pleosporales. In the pdf-file I published a meta-analysis in which you find a list with the most common causative agents. Since then I have updated this list and it includes more than 10,000 cases now. However the order of causative agents is roughly the same. vandesande-2013-PlosNeglTropDis7-e2550.pdf

Only problem with this list is that it was based on historical data. Since then we have discovered that even in the large culture collections many misidentifications have occured. Therefore for eumycetoma we recommend to use ITS sequencing instead of culture or histology as more reliable. looking back at the data and with the information we have on the data from culture collections, the most common found causative agents of black grain mycetoma are:

• Madurella mycetomatis (most common in the world)
• Falciformispora senegalensis (very common in western Africa)
• Trematosphaeria grisea
• Medicopsis romeroi (in vitro resistant to itraconazole)
• Nigrograna mackinnonii
• Falciformispora tompkinsii
• Madurella pseudomycetomatis
• Madurella tropicana
• Madurella fahalii (in vitro resistant to itraconazole)

For white grain mycetoma Apiospermum boydii is most common. However, this fungus can cause many other fungal infections as well. The fungi mentioned above are only implicated in mycetoma or some also in chromoblastomycosis.

[MFernflower]

Indeed those names are quite old but wikipedia is pretty decent at archiving the old names before one name one fungus.

[wwjvdsande]

The names of the fungus were up to date. The only problem is that they were identified based on culture or histology. We now have learned that when we sequence these fungi, many misidentifactions have occured. Even the large culture collections such as the britisch and french culture collections had many eumycetoma causative agents misnamed in their collections as demonstrated by andy borman. Problem is that they often do not sporulate. However, for these fungi we also have assays up and running. So it should not be to difficult to test the fenarimols against them.

[MFernflower]

@wwjvdsande Sorry I didn't touch on this for the last meeting - Are you able to do a broad fungal panel or should we just focus on the big three: Madurella mycetomatis, Falciformispora senegalensis and Pseudallescheria (Apiospermum) boydii

[MFernflower]

@wwjvdsande @bendndi @mattodd If our drug say only kills Madurella mycetomatis and Pseudallescheria (Apiospermum) boydii but is rather useless for other organisms - would that count as a win?

[wwjvdsande]

@MFernflower @bendndi @mattodd. Of course the most ideal drug would be a drug which

1. kills or inhibits all mycetoma causative agents
2. penetrates the grain to reach the pathogen inside
3. is able to cure eumycetoma without the need of surgery

However, if we do not find this ideal drug yet, a drug which can do all of the above only for Madurella mycetomatis is already worth it. Madurella mycetomatis is by far the most common causative agent of fungal mycetoma. In that case identification of the causative agent would be key before treatment starts but that is not undoable.

To be able to treat mycetoma with a single drug would be nice, but remember actinomycetoma is always treated with a combination of 3 drugs. So if we have drugs with different modes of action active against fungal mycetoma that would also be good.