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News
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
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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.
References
[1] WHO Global Action Plan on Antimicrobial Resistance.
http://www.who.int/antimicrobial-resistance/en/
[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)
http://link.springer.com/article/10.1007/s13659-020-00280-y
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