Gathering data on newly synthesised fenarimol analogues

[laujialiang]

Hello @wwjvdsande , I am Jia Liang from UCL, currently in my final year under MPHARM programme. I am currently working on a research paper with the aim of confirming the conclusion proposed by Rosalyn back in 2019 #22 where she mentioned that compounds with lower Log D value at pH 7.4 are more likely to have better in vivo efficacy in treating the eumycetoma grains. So, I am wondering if I could get some newer data where she has not used #23

I have already looked at the megathread #29 but the information included is only the Target ID and Log D value, without the percentage survival which is important to highlight the significance of Log D value.

I have also come across a research paper with a table as shown:

So, I am wondering if 30% is good enough to be counted as being able to penetrate through biofilm? If it is, then I could collect the Log P value of the compounds from PubChem and identify if there is any significant correlation between Log P and the ability to penetrate.

[laujialiang]

I have made a table with the Log P values. From the table (without plotting a graph yet), XLogP3-AA > -2.6 means the antibiotic is able to penetrate, where ampicillin is an anomalous. Log P > -0.58 means able to penetrate, where vancomycin and ampicillin are the anomali. I feel that the Log D values would be more accurate to elucidate the relevance of lipophilicity and biofilm penetration, however, I was unable to locate the data online. As an expert in this field, would you be able to shed some light into this? Are there any ways I could get the Log D values of these compounds? @bendndi @wwjvdsande

[Wilson-Lm]

Hello @wwjvdsande , I am Jia Liang from UCL, currently in my final year under MPHARM programme. I am currently working on a research paper with the aim of confirming the conclusion proposed by Rosalyn back in 2019 #22 where she mentioned that compounds with lower Log D value at pH 7.4 are more likely to have better in vivo efficacy in treating the eumycetoma grains. So, I am wondering if I could get some newer data where she has not used #23

I have already looked at the megathread #29 but the information included is only the Target ID and Log D value, without the percentage survival which is important to highlight the significance of Log D value.

I have also come across a research paper with a table as shown:

So, I am wondering if 30% is good enough to be counted as being able to penetrate through biofilm? If it is, then I could collect the Log P value of the compounds from PubChem and identify if there is any significant correlation between Log P and the ability to penetrate.

Dear JiaLiang, I'm quite happy to hear you are continuing/confirming Rosalyns work. I have read her thesis and found what she did really interesting. Her work gave us some ideas on how to play with data.

Happy to aid you where you need, I have full data of the pandemic box and the fenarimol compounds that we have tested in 2020. These new data - %survival and Log-Rank, i have uploaded it into the spreadsheet we have on Github. (https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=954203120) Data is on the Pandemic response box and the MyOS compounds (fenarimol analogues) sheet.

I am currently looking into the relation of LogD, MW, AUC values to %survival of compounds in the Pandemic Response Box and that may be of your interest. I will most likely present my conclusions in the next MycetOS meeting, so do join in and listen.

[Wilson-Lm]

I have made a table with the Log P values. From the table (without plotting a graph yet), XLogP3-AA > -2.6 means the antibiotic is able to penetrate, where ampicillin is an anomalous. Log P > -0.58 means able to penetrate, where vancomycin and ampicillin are the anomali. I feel that the Log D values would be more accurate to elucidate the relevance of lipophilicity and biofilm penetration, however, I was unable to locate the data online. As an expert in this field, would you be able to shed some light into this? Are there any ways I could get the Log D values of these compounds? @bendndi @wwjvdsande

Larvae survival % is most certainly likely linked to the ability of a drug to penetrate the grain, so it would be really interesting to know if there is any even a better correlation of LogD to %survivil or LogP to % sruvival. The LogD values for the fenarimols will be calculated shortly, but you can easily obtain LogD and LogP values for pandemic box compounds we tested in vivo and compare and see if D or P is better correlated to survival %.

[laujialiang]

Hello @wwjvdsande , I am Jia Liang from UCL, currently in my final year under MPHARM programme. I am currently working on a research paper with the aim of confirming the conclusion proposed by Rosalyn back in 2019 #22 where she mentioned that compounds with lower Log D value at pH 7.4 are more likely to have better in vivo efficacy in treating the eumycetoma grains. So, I am wondering if I could get some newer data where she has not used #23 I have already looked at the megathread #29 but the information included is only the Target ID and Log D value, without the percentage survival which is important to highlight the significance of Log D value. I have also come across a research paper with a table as shown: So, I am wondering if 30% is good enough to be counted as being able to penetrate through biofilm? If it is, then I could collect the Log P value of the compounds from PubChem and identify if there is any significant correlation between Log P and the ability to penetrate.

Dear JiaLiang, I'm quite happy to hear you are continuing/confirming Rosalyns work. I have read her thesis and found what she did really interesting. Her work gave us some ideas on how to play with data.

Happy to aid you where you need, I have full data of the pandemic box and the fenarimol compounds that we have tested in 2020. These new data - %survival and Log-Rank, i have uploaded it into the spreadsheet we have on Github. (https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=954203120) Data is on the Pandemic response box and the MyOS compounds (fenarimol analogues) sheet.

I am currently looking into the relation of LogD, MW, AUC values to %survival of compounds in the Pandemic Response Box and that may be of your interest. I will most likely present my conclusions in the next MycetOS meeting, so do join in and listen.

Hello Wilson, first and foremost, thank you for the great help. I have looked into the spreadsheet Pandemic response box and the MyOS compounds but I couldn't find the Log D value column, only the Log D p-value that is located next to the % survival. I have compiled the new data that was not included in Rosalyn's thesis in the In vivo potency & Log D values from row 28 to 54. Sure, I will try to attend to the meeting.

[wwjvdsande]

@laujialiang I think that for each biofilm the data will be a bit different. For that paper 30% penetration might have been good, however we don't know if similar percentages can be reached in a grain. Bacterial biofilms and fungal biofilms have a different composition and the true composition of the mycetoma grain is not known. However you need to start somewhere, so why not use the data they have. However don't compare penetration in biofilm and larval survival head on, they are not the same of course.

[laujialiang]

@wwjvdsande Thank you for your feedback. Currently, I have also included chemical formula and structure (to identify any important functional groups), molecular weight (found out a huge vancomycin [MW=1449.2] can penetrate, while a much smaller ampillicin [MW=349.4] is unable to do so) and physiological charge (a trend where compounds with a high ratio of positive physiological charge:MW such as gentamicin and tobramycin are unable to penetrate). Also, since EPS retains a large amount of water within the matrix (https://pubmed.ncbi.nlm.nih.gov/23545571/), is hydrolysis inevitable for any compound that passes through? If it is, will the antibiotics (such as B-lactams) that can pass through biofilms still show low efficacy due to the hydrolysis of B-lactam group?

[wwjvdsande]

@laujialiang That is possible. Penetration inside the biofilm is step one, but for fungi (See chapter 133 from the Manual of Clinical Microbiology for instance) and probably also bacteria, efflux pumps are also upregulated. So if a drug penetrates inside the matrix and cell, it is also effectively pumped out.

[wwjvdsande]

@laujialiang the thing with biofilms is that they also allow tolerance to drugs.This could give the bug also enough time to create some resistance by changing its target molecule as well. A biofilm is a mixed culture in the end. So some individuals might become metabolic dormant, others might be metabolically active, others can mutate and others might produce some stress responses beneficial for the whole community. So it is a tricky task to find a simple rule because all these factors might contribute. E.g. if logD is beneficial in general, may be some compounds with a LogD which we expect to penetrate might in the end penetrate but still not reach the internal target due to some other factors (e.g. the size, or it becomes a target for an eflux pump). However, taken this in the vback of our mind, we need to start somewhere and any rule we find might help us in the design of new molecules. May be also an idea to look at efflux pumps and see if there is a difference in structure linked to that as well. It is just a thought which now popped up. Did not explore this further

[laujialiang]

@wwjvdsande Yes, I am aware of the significance of the efflux pumps, especially in fungal biofilms such as C. albicans where the efflux pumps are upregulated within the first few hours of adhesion and remain upregulated throughout biofilm development, even in the absence of an antifungal drug. I just thought about hydrolysis because it may be ubiquitous in all biofilms since microbes require water to survive, maybe it could be something to consider when synthesising new compounds.

Thank you for your explanation, much appreciated!

[wwjvdsande]

@laujialiang, may be the model should be an equation or something. I know we don't have enough data on it. But may be it should be LogD + Mw + LogP or something like that. So the LogD should be between this and that, the Mw should be between ... A collegue of mine works with S. aureus biofilms he thinks charge of the molecule is important. At least in his biofilms. So may be that is another angle to look at. I don't think we did add or calculate the netto charge

[laujialiang]

@wwjvdsande I found out the ratio of physiological charge to density is an important factor based on my data too, but they are just antibiotics so I am not really sure if the same could be applied to M. mycetomatis. I have read from some papers that the eDNA (negatively charged) within the matrix could bind to positively-charged molecules, and from all the biofilms I have looked into, they all have eDNA and I am thinking maybe this is why the charge plays a role.