Activity leads. Structure follows. Nothing is claimed before both agree.
Photograph · Unsplash
Approach
Our experimental logic is bioassay-guided isolation: let biological activity tell us which fraction to keep, and only then determine what is in it. It is an old discipline and an unglamorous one, and it is the reason our results hold up.
Activity leads. Structure follows. Nothing is claimed before both agree.
Working principle
A hit is a hypothesis, not a result.
Biological material is chemically crowded. A crude extract contains hundreds of compounds, and any observed activity may come from one of them, from several acting together, or from an artefact of the extraction itself. The purpose of our workflow is to close the gap between this extract does something and this compound does this thing, for this reason, reproducibly.
Each round of separation is followed by re-testing. Fractions that retain activity are carried forward; fractions that lose it are set aside and, where the loss is informative, examined. Activity is the selection pressure on our own workflow, applied repeatedly, until what remains is simple enough to identify with confidence.
Practice
The historic failure mode of natural-product research was investing months in a compound that turned out to be well described in the literature. We treat identification as an early screen rather than a late reward: chromatographic and spectral profiles are checked against public data as soon as a fraction shows reproducible activity.
Recognising a known compound early is not a disappointing outcome. It is a cheap one, and it is what allows resources to concentrate on the fractions that remain unexplained.
Chromatographic separation coupled to high-resolution mass spectrometry gives accurate mass and fragmentation behaviour, and with it a defensible account of what a compound is rather than a plausible guess. Where the class of chemistry requires it, orthogonal methods are used to confirm rather than to corroborate.
The standard we hold to is straightforward: if we cannot say what a compound is on analytical evidence, we do not describe it as characterised.
Susceptibility work is run against defined reference strains under standardised conditions, with positive and negative controls on every plate, in replicate, and by methods that another laboratory could repeat from a written protocol. Where activity against a clinically relevant organism is claimed, it is that organism that was tested, not a convenient surrogate.
Selectivity is measured alongside potency from the outset. A compound that kills everything, including host cells, is not a lead — it is a disinfectant, and we would rather establish that in the first month than the twelfth.
A single observation is a starting point. Activity is confirmed across independent preparations from independently sourced material before it changes what we work on, because natural material varies with season, source and handling, and a result that depends on one batch is a property of that batch rather than of the chemistry.
The same applies in reverse. Negative results are recorded and kept, since knowing where activity is absent is what makes the map worth having.
Principles
A compound is interesting when the data says so, not when the story is good. We would rather end a line of work early and cheaply than carry a comfortable assumption forward.
We are not looking for a novel approach to discovery. We are running a well-understood one properly, with the tools that removed its historic bottleneck.
The science decides direction. Those decisions are made by the people running the experiments, not around them.
Activity without an explanation is a result that cannot be built on. We want to know why a compound works before we argue that it does.
Early chemistry is fragile. We publish areas and reasoning, not compounds, and discuss specifics only under agreement.
The biological material is here, the research ecosystem is here, and the resistance burden our anti-infective work addresses is heaviest here.
Collaboration
We are interested in talking to laboratories with complementary analytical or assay capability, to clinicians and microbiologists with access to relevant isolates, and to researchers working on adjacent biology.