Open Source Antibiotics Series 1 - the Mur Ligases, 9 Mar 2021

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From YouTube: Open Source Antibiotics Series 2 Mur Ligase Update Mar 9th 2021

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Open project meeting for Open Source Antibiotics Series 1, the Mur Ligases.
Full Project: https://github.com/opensourceantibiotics/murligase
Relevant GitHub Issue: https://github.com/opensourceantibiotics/murligase/issues/40
On the call: Professor Matthew Todd, Dr Dana Klug, Yuhang Wang (UCL), Professor Chris Dowson, Laura Diaz Saez (University of Warwick), Lizbe Koekemoer, Gustavo Arrudabezerra (Diamond/Oxford), Bart Staker (SSGCID), Joe Eyermann (NEU), Jan Jensen (University of Copenhagen), Peter Horanyi (UCB).
Partial recording, forgot to switch on, sorry...

A

Perfect, it's going to make no sense, but the recording is on principle now now you've said that.

A

So yes, all of this is public domain stuff. For sure I mean that's one of the things about it, so yes, it's very, very much in line with with what you guys are doing with the structures. Of course,.

B

Great yeah, that's that's great yeah, because it's um that's! Our goal is to help the public domain.

A

All right, okay, will you come to the right place.

B

Can I introduce you to laura, while you're here so laura's working with me on the structural biology- and I guess lisby is potentially still a little bit perhaps interested in this, but yeah laura is actively doing this. So just make sure that you, you know if she's willing or able to hook up with you too just sure you know, learn some tips and that would be fabulous. Yeah sure thing, yeah.

C

Yeah uncoordinated, maybe we could have another meeting another time, but I have set up crystal place for mule c april, the same ones that I am we use for the x-cam screen. uh So that's reproducible. I can get crystals, that's fine and I'm planning to do neody next week, so we can also have those for soaking but yeah. Maybe we can it took a bit, and these are e coli mursi.

A

Happy to help um just just on the updates um in that case, just since we're talking about the compounds um going to you guys, joe did you have any news on the on the az compounds or how that's going.

D

uh I I've kind of dropped the ball here, so I've been working kind of on the innovation proposal, but I haven't finished it so so bart put together an initial template and I've been working on that, but I haven't actually sent it back to him yet um so we're we're we're behind in that. So I'm that's the one where I kind of haven't delivered what I should have done so there's something hopefully get back to them soon. um Okay,.

B

Great so request.

D

Is it's got to go in correct, yeah requests will go in yeah.

E

Well that, I think that's I mean we made some progress after last meeting, where we we got started on it's a whole like little application. That requires aims and all this stuff, and so we got started um on it. And hopefully uh you know we got a little momentum and then I think we got busy with yeah.

D

Probably I'm probably.

E

Never really worked on a little bit of overkill, so I'm probably.

D

Doing overkill on how much um detail I'm putting in there, but anyway um yeah, we will finish it up.

B

Yeah and and we've now got the uh mta from astrazeneca and it's now filtering its way through uh the very fine sand filter that is the uh sign-off process at warwick. For that, so it's on the way.

A

Okay, um that's good to know the um I mean. Obviously, those compounds are really going to be crucial. um I'll just share uh the the slide that uh that is has put up on the github issue. So you hang um started this synthesis of the iso compound you ain't did you want to say just a little bit about what you're up to.

F

Yeah, it's fine as long as the noise is not too loud. Is that fine, okay cheers so uh I've been I've been doing the first step uh from compound one to five uh trying to synthesize the parasol aiming uh trying to synthesize the parasol aiming ring uh uh in which the the two of the nitrogens will will interact with near c.

F

That's why we're using that, and uh especially the first step, especially the first step synthesizing that ring is a bit challenging for me, maybe because it's a whole new, uh uh it's a whole new uh strategy. uh I guess uh there are not not that many references before uh but from after we synthesize that uh from compound five well, we can just go all the way to to the asia compound 5.95, because those those procedures are referenced in uh in that paper.

A

So we this is, this is cooking and this was bought.

A

Yeah yeah right and these two steps should be fairly well behaved, yeah exactly all right great, um so we should be able to get this camera pretty soon provided this first step works, and I guess we'll find that pretty soon.

F

A

Okay, great, that's the first thing just to get that compound, ready in quantity.

G

I'm just going to to mention um I've made a lot of um amino results. So if you wanted to, if you're having issues with the chemistry feel free to touch base.

A

Oh, that's great. Thank you, lori. That could be very useful. That first steps. Just I mean it's just it's a stew up and if it comes out good, it's all fine, but if it doesn't, it could be around that.

G

Yeah I mean the the it does have a tendency to decompose on you, so yeah happy to help. Thank you.

A

Thank you all right, and then I um so I guess just going back to what you were talking about laura in terms of uh you know, crystallization trials. Soaking compounds. Do you want to just say where you're up to with with what you were, I guess just expanding on what were you just saying about the mercy and the crystallizations and trials.

C

So I have basically a system ready for mercy for the apo. I also got crystals in the presence of magnesium as well, because the initial crystals didn't have function, so I just decided to do a small test, so I I am planning to go on april to dry, monitor khan and test crystals on a small portion of the library and see if we can get different hits in the presence of magnesium and I'm also setting up some plates.

C

Well, they already set up just nothing really so far and with a mercy and some ligands to see if we can get a more close conformation and see if that will give a more reversible compounds that will bind to different conformation of the protein um and then currently that so, if anything grows, I'm gonna follow it up and see if I can get it ready for xcom. Basically again, my aim is having these uh in mid april, so they can be tested on diamond after the shutdown and and yeah. And then I do.

C

I want to do like a small um scale, fragment screening soaking um and see if they will be feasible for future work. That's my plan, yeah uh diamond shutdown. So what's that and shut down, I think it's coming back on 12th of april is happening now, if I like and next week, if I were correctly then 12. the.

H

Synchrotron shuts down for a month, routine maintenance, and we can't do any crystallization collections yeah this week is the last week that we have been time and then goes down. It comes back.

C

H

C

The last crystals you were accepting were um last week last friday, so there was no time for me to do anything like that.

A

That must be like torture, for you guys.

H

It's some time.

A

H

You got some time to process.

A

Finally, you can stop all the data coming out. We.

C

Find protein time now.

C

Okay, yeah and basically I want to get also the pistols that were used for x for mule d. I want to get those set up as well, so if we get any any hits from the essays from becca, then we can set some crystals as well. Okay, I want to start it next week. If I can't so.

A

um I mean so if we make the astrazeneca standard compound the one that's currently in the mercy structure the peta solved, I guess you could do some of that as like a positive control. Is that helpful? Okay.

C

Exactly yeah, I can do.

A

Okay, great thanks um and then I guess, speaking of beccah she's, not with us chris dude, would you are you able to update on any uh any stuff to do with with that project?.

B

um um I was thinking she would be here, so I didn't prepare anything. No.

A

That's fine, don't.

B

Put you on the spot. I.

C

I have talked to her last week about it and she she said she was planning to do some screams. I have compounds not this week next week, but it was happening soon. That's what she told me about a I don't know. If things have been worked in uh working on us, he was expecting.

A

Okay- and these are I mean these are hits- there are some that lisbeth would send, and obviously the stuff that dana previously sent yeah.

C

They are compounds and all the components that were sent, yeah wow all right yeah, so hopefully we'll have that soon. uh If everything works. Obviously I don't know if that worked. um I briefly saw her today, but I wasn't able to um have more discussion with her because I was in a hurry.

A

Great, thank you all right, wonderful, um all right! So as far as I can tell, if I just already look at my own agenda- um oh I was going to mention something about the atomizer compounds still not got legal approval, I'm getting a few questions from ucl legal people about whether we need a an mta to send compounds to warwick and diamond, and I'm emphatically saying no, we don't um to try to speed things up because it's all open and everyone is agreed by email, what's needed and so on.

A

So I'm I'm trying to say that, but all we need is the uh assurance that atomwise needs from us between ourselves. So I think the last thing is that email from summoner warwick, I think, there's an email exchange a couple of days ago about this. We need that last email from from someone at work to agree to the terms in the way that diamond has, and then that puts the onus squarely back on ucl. To get this sorted out.

A

I mean the compounds are in the freezer, but the last thing we want is any sense of doubt about their integrity. So we want to make sure this happens soon.

A

As far as I can tell it's a very, very small paperwork hill and I don't want it to grow um so I'm doing all I can on that, but it's still proving to be a little bit slow. um Any mta will slow things down by you know a month per partner and I'm just trying to emphasize that.

A

I don't think we need one here, because everyone understands what the compounds are and what the requirements are and we don't need a contract for that, but we'll see, um and then I think everything else was um has been dealt with as far as I as far as I can tell um so, does anyone have anything else that you'd like to mention that I haven't mentioned.

B

um Got some more money so got another 10 000 pounds for chemistry that came through from warwick innovation.

B

Almost almost almost almost got the uh the 50 odd thousand pounds for uh adrian for next year and laura doesn't know this, but I've put in some money for her for another four months as well. So I'm just writing. Writing that at the moment, so yeah there's a slew of stuff happening locally, that this fits in really well for so fantastic yeah, so um yeah yeah, that's all good.

A

Good stuff, fantastic, great.

A

Okay, if that's everything, then that's really good. um Hopefully we'll make progress on all these various ones. I'll write up the action items in the meeting and just keep people in touch, and then um I'd suggest we meet again in a month. Hopefully we'll have something else to report. We do have easter in the way.

A

um So if, while I just have you on the line here, um it would just be very helpful rather than doing any moodle horrors, it would be very useful if we could just approximately say that 2pm april 13th would be okay.

A

Should be that, generally, all right.

E

For everybody, that's fine, it's all thumbs up. Is that the same time as this just like they can't do time zones on the fly all right actually.

D

What we want to do we're going we're going to change the clocks next week, so it'll I mean it'll be the same time. It's just um well. Actually it won't be well. Is that.

A

Worse, for you.

D

uh We're we're springing ahead so right now, instead of it being 9 29 here, it's 10 29, so um so actually it'll it'll be better right, so you'll be starting an hour later. Is that right, we're springing ahead too.

H

E

Yeah, I think we also do daily time these days. I'm not sure what happens um so either. Time is good for me. It's just okay,.

A

Okay, I'll stick it at the usual time and then, but if it's really getting painful, we can shift it.

A

Okay, wonderful thanks for coming! Everybody really appreciate it and uh yeah I'll be in touch after this meeting.

B

Yeah yeah. Thank you all.

A

Right, nice to see everybody see you next time. Thank you, bye-bye four o'clock. Chris got it thanks.