General or specific TPP?

[danaklug]

Issues around TPP have already been started (#9 #10 #11); however, these may need to be more specific to really be useful. Therefore, some questions that need to be addressed include:

• Should we focus on MRSA or try to develop a broad-spectrum antibiotic?

• What is the targeted route of administration?

• Should we develop separate TPPs for different stages of the project (i.e., start with minimum criteria and get progressively stricter?)

• Are there TPPs that have already been developed as standard for antibiotic drug discovery that we could use as a starting point?

To help us define a TPP, we should come to a consensus on answers to these questions that give us the best chance of successfully developing a useful compound. Any additional input/expertise here is very welcome!

[drc007]

This is a really important question and should apply to all Open Source Antibiotics projects.

I’m sure everyone would like a broad-spectrum agent that can be used oral, iv or topical, with a high degree of safety for all indications, with no resistance.

The reality is we will need very different properties depending on the indication, for urinary tract infections we would want extensive renal unchanged clearance, for chest infections we would want the drug to localise in the lung, for skin infections we might want topical treatment with little systemic exposure.

I’ve put together a table of the most important pathogens as defined by WHO, and then annotated with what I can discover about each pathogen, some look to be more important for specific indications.

Antibiotics.xlsx

Everyone I know who has been taken to hospital with an infection has been put on intravenous antibiotics for a couple days to start with. Should we be looking at use in intensive care as the likely place for introduction of a novel antibiotic? Is it likely that to reduce the chance of resistance and novel antibiotic would have restricted use? This would obviously be a major consideration for a commercial programme but can we approach this differently?

Rather trying to cover everything, should we be focussing on a specific need?

[danaklug]

@drc007 Excellent points. I’m thinking of something like the below as a starting point, with “acceptable” properties being our first target and then converting to “ideal” if we can.

• I think it’s advisable to focus specifically on MRSA activity in the beginning, given that the focused array compounds weren’t active against the other ESKAPE pathogens and that this is the assay we have online. There are strategies we can pursue down the line to convert a compound with Gram-positive activity to a broad-spectrum compound (i.e. trying to conform to the guidelines Paul Hergenrother’s group has come up with).

• I’ve had a look at the current drugs used to treat MRSA infections and most cause multiple, albeit mild, side effects routinely. There are also some more severe effects in some patients that require monitoring or restricted use. Ideally we would be aiming for something non-toxic but it seems that these infections are serious enough that there is some leeway here.

• It looks like, at least in the UK, that oral drugs are preferred for first-line treatment but IV or IM administration is acceptable. Again, we could look at modifying physicochemical properties at a later stage to potentially convert to something that is orally available.

• We don’t currently have a cidal/static assay so this may not be useful to include – or it could be something we evaluate at a later stage.

• I’m not necessarily sure that a monotherapy is inherently more desirable than combination therapy (although at point of use it would probably be cheaper) – thoughts?

These parameters are meant as a starting point and I’m more than happy for others with more expertise than I have to suggest adjustments. @bendndi Is this something that DNDi would be willing/able to chime in on?

Where I think a TPP would be most useful is in helping us define target values for the assays we do have, so that we have benchmarks against which to evaluate our compounds. The project is currently set up as shown below with the data we have to work with. I’d also like to fit a toxicity assay in (ideally Tier 1 but at least Tier 2). So the question is: what values should we be aiming for in these assays to achieve an “acceptable” profile and what values should we be aiming for to achieve an “ideal” profile?

Sorry for the long post – hopefully I’ve been clear and useful! Further discussion definitely appreciated!

[drc007]

I've added the GARDP discussion that included mention on TPP.

https://github.com/opensourceantibiotics/GeneralTopics/issues/3#issuecomment-647384679