Last week (during my vacation), Losee Ling, Kim Lewis and their
collaborators published a
paper in Nature that was picked up by the world’s press – and deservedly
so. But most of the news articles missed
the key point – at least to me.
What the press focused on was the new antibiotic discovered and described in the paper, called teixobactin. It turns out that teixobactin represents a new class of antibiotics that
binds to the bacterial cell wall and thus inhibits further synthesis of the
cell wall. This mechanism is similar to
that of vancomycin, teicoplanin, dalbavancin and other glycopeptides, but
teixobactin has a completely novel structure. Teixobactin was even active in a
mouse model of infection. If it ever
gets developed, it will be only available by intravenous (maybe intramuscular)
injection and will only be active against Gram-positive pathogens including
superbugs like MRSA.
Teixobactin itself, in spite of all the hype, is not so exciting to me. First, Gram-positive pathogens, even the MRSA superbug, are not the area of major medical need right now. We have lots of old and new antibiotics active against these organisms. We need new drugs active against Gram-negative pathogens like the carbapenem-resistant superbugs now plaguing patients and physicians around the world.
Also – antibiotics like teixobactin are a little like old
news. We at Wyeth, and many pharmaceutical companies during the 1990s, carried
out programs where we re-examined our collections of natural products going
back to the 1940s when soil was being collected from around the world and
screens based on microorganisms from soil were used to identify new
antibiotics. We discovered an old natural product sitting around on our shelves
since the 1960s called mannopeptimycin.
The extract from the culture of the producing strain was active in vivo
in a mouse model just like teixobactin.
And mannopeptimycin bound the cell wall in a way that resembles
teixobactin. Alas, mannopeptimycin
caused severe inflammation of blood vessels in animals both at the site of
injection and at distant sites and could never progress into clinical trials. The
fate of teixobactin remains to be seen as further studies of the safety of the
new product are carried out.
But lets talk about the most exciting aspect of the discovery
– the new method for finding new antibiotics. The way Ling et al found
teixobactin is novel, simple and may pave the way to a whole new generation of
new antibiotics from soil microorganisms. If you think about it, microorganisms
from soil were and are the source of most of today’s antibiotics starting with
penicillin, cephalosporins, strepotomycin all the way through tetracyclines,
erythromycin, vancomycin, daptomycin etc. But its been estimated that you can
only grow less than 1% of microbes that live in soil using normal culture
media. And to extract antibiotics from
the soil, you have to be able to grow them. What Ling et al did was to take
soil samples and dilute them such that they would introduce about one bacterial
cell in a test tube with a membrane bottom.
This membrane would allow nutrients to flow into the test tube. The test tube (in this case actually a small
plastic well) was then placed back on the soil from which the original
dilutions had been made. This would
allow about 50% of the organisms to grow – presumably getting key nutrients
from the soil that are not present in normal culture media. Ling et al could
then extract the growth media from these test tubes to identify those
containing products that would inhibit the growth of other bacteria – that is –
antibiotics. They came up with teixobactin. By carrying out such a screening campaign using large automated
systems and many soil samples, someday, we might even be able to find new
antibiotics active against the Gram-negative pathogens where our medical need
is the greatest. To me, this is the key
finding of the paper, not so much teixobactin.
My hearty congratulations to Drs. Ling, Lewis and their
entire team!
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