The discovery of Penicillin in 1928 ushered in the golden
age of antibiotic discovery with most of these being introduced in the
1950s-1970s. Since then there has been a dramatic decrease in the number of new
antibiotic classes coming to the market.
After the 1960s focus changed from developing new classes of
antibiotics to the production of semisynthetic drugs based on previously known
classes, this managed to keep up with the development of resistance until
Modern antibiotics fall into 3 categories.
Natural products are antibiotics obtained from natural
sources such as benzylpenicillin from fungi.
Synthetic antibiotics are discovered either by rational design
and high throughput screening programmes or by accident in the production of
other drugs and chemicals.
Most antibiotics currently in use come from the third
category; semisynthetic antibiotics. These ar
e derived from natural products but have been chemically
modified to: improve the spectrum of effect, bypass resistance mechanisms or improve
Most natural product antibiotics currently in use come from
soil actinomycetes and over 28,000 compounds have been identified so far with
around 200 finding direct use as drugs.
Natural products have many advantages; They are the product
of millions of years of evolution allowing them to bind in an extremely
effective and specific manner. They also inherently have the physiochemical
properties necessary to reach their target.
There were several problems with previous methods of natural
99% of actinomycetes are fastidious, meaning they do not
grow in lab conditions. Of those that do grow, many of them will not produce
antibiotics under these conditions. even if they do produce an antibiotic there
is a distinct chance it is one that we already know about and dereplication of
these takes time and resources. Because Actinomycetes have been so thoroughly
studied it is getting harder to find novel products from this source.
Genus and species-specific inhibition would often go
unnoticed as the colonies were tested in simple colony based assays against
only a few species of bacteria including: Escherichia, Bacilli and
Newer methods use the mostly automated and much faster
process of high throughput screening to test for antibiotic behaviour against
many different species of bacteria.
The iCHIP allows for cultivation of previously unculturable
strains. It consists of hundreds of individual wells separated from their environment
by a semipermeable membrane. This allows bacteria access to the chemicals in
their natural environment without allowing contamination of the sample by other
bacteria. This allows up to 50% of actinomycetes strains to grow.
The iCHIP was essential in the identification of Texiobactin
Teixobactin Inhibits cell wall synthesis by binding to lipid
II and lipid III, this gives it excellent activity against Gram positive bacteria
even in low doses.
Genome sequencing allows the identification of silent biosynthetic
gene clusters which can be activated to produce products by changing
intracellular conditions or through various chemical genetics techniques.
High performance liquid chromatography is a technique used
to separate, identify, and quantify each component in a mixture.
This separation technique coupled with improved methods of
analysis such as Mass spectrometry, NMR and circular dichroism spectra allow
the rapid separation and characterisation of organic compounds. This massively
speeds up the process of dereplication
Although most natural product antibiotics have been
identified from soil actinomycetes, it is also important to look at other
sources as well.
Marine actinomycetes show promise, as do fungi, plants and commensal
bacteria. Last year, A team from the university of Tübingen in Germany
discovered the antibiotic Lugdunin. It was produced by a commensal strain of S.
lugdunensis and inhibited growth of pathogenic S. aureus.
Synthetic antibiotic discovery is usually done using
rational design campaigns, so, identifying key genes, producing the gene
product and using throughput screening to find an inhibitor.
The major drawback with this system is low in vivo efficacy
due to problems in bacterial cell penetration. and decreased cell penetration
means a higher dose of the drug is required increasing the chances of toxicity.
There are several ways to improve bacterial penetrance:
smaller, hydrophilic compounds can pass through membrane
porins. Removal of cations and hydrophobic regions or addition of non-organic
molecules can allow evasion of efflux pumps. Allowing the drug to accumulate
sufficiently to have an effect.
Current screening methods are simplistic and do not account
for bacterial penetrance. Screening compounds for whole cell effectiveness or
using animal models such as The Nematode Caenorhabditis
elegans allow screens to better replicate the conditions in an infected
Bedaquiline was discovered as part of rational design
campaign by Janssen Pharmaceutica and was approved for use in the US in 2012.
It was the first new medicine for treating multidrug resistant TB in over 40
years. It targets the Mycobacterial ATP synthase and inhibits production of
ATP. This allows killing of both replicating and non-replicating bacteria which
Hannah will expand on.