Caithness Biotechnologies: Natural product libraries for drug discovery Harnessing Nature for drug discovery
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A screen of our Phytotitre library reveals new hits for Alzheimer’s disease

Nobel prize awarded for natural product-based drug discovery,

Discovery of new class of antibiotic through innovative natural product library screen,

No decrease in rate of discovery of new natural product scaffolds between 1990 and 2015


Natural product libraries for drug discovery


A screen of our Puretitre library reveals new ways to reverse antibiotic resistance

The emergence of bacteria which are resistant to multiple antibiotics is an increasing concern for global healthcare systems. Historically, this issue has been countered by the discovery and development of new classes of antibiotics. However, as resistance to these new antibiotics frequently emerges within several years of their introduction [1], attention has focussed more recently on the identification of agents that block the mechanisms used by bacteria to resist the effects of the antibiotic.

So-called “resistance reversing” drugs have been successfully deployed in the clinic to treat infections where the chief mechanism of resistance is via overexpression of enzymes that break down antibiotics of the beta-lactam family. For example, the combination of amoxicillin with the natural product clavulanic acid (together called Augmentin) works much more effectively than amoxicillin alone when treating infections with bacteria expressing lactamase enzymes as their chief means of resistance. However, there are many other mechanisms by which bacteria resist antibiotics, and lactamase inhibitors are not effective against these other forms of resistance.

In a recent screen of our Puretitre library of 200 natural compounds, 4 hits were discovered to significantly inhibit the resistance of a clinically relevant strain of Escherichia coli to the antibiotic tetracycline [2]. The strain examined is a clinical isolate that commonly causes urinary tract infection in man, and is resistant to many different classes of antibiotic. Further study of these hits showed that they were also effective at reversing resistance to antibiotics of several other classes, including chloramphenicol, trimethoprim and tobramycin. One of the hits, cepharanthine, was found to potently inhibit molecular efflux from the resistant cells - a commonly used method of resistance in such microbes. Notably, very few inhibitors of Gram-negative efflux pumps have been discovered previously. Two of the other hits, propyl gallate and ellagic acid, significantly inhibited the uptake of nutrients into the cell, and slowed the rate of growth of the resistant bacteria.

Preliminary studies of the potential toxicity of the compounds revealed that three of the top four hits (propyl gallate, ellagic acid and cinchonidine), showed negligible toxicity in an in vitro mammalian cell culture model, at doses higher than those required to block resistance. This is consistent with the use of propyl gallate and ellagic acid as approved food additives in some territories, and the rationale for the library of focussing on plants with a history of safe oral use in man. By screening collections of molecules with low toxicity from the outset, the aim is to accelerate progression of hits from such screens to animal studies or nutraceutical trials.

The relatively high hit rate of this screen (~4%) also suggests that traditional medicines may be richer in molecules with antibiotic potentiating activity than previously thought. Therefore, although there are many other potential mechanisms of resistance waiting to be explored, it is likely that natural product screening could provide useful structural leads for the development of new drugs to target resistance to multiple different classes of antibiotic.

[1] WHO Global Action Plan on Antimicrobial Resistance.

[2] Jenic et al, Reversal of tetracycline resistance by cepharanthine, cinchonidine, ellagic acid and propyl gallate in a multi-drug resistant Escherichia coli. Natural Products and Bioprospecting (2020)


Hits from the recent Puretitre screen

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