New antibiotic in
30 years discovered in major breakthrough(Texiobactin)
Introduction
The first new antibiotic to be discovered in nearly 30 years
has been hailed as a ‘paradigm shift’ in the fight against the growing
resistance to drugs.
teixobactin has been discovered by scientists who claim it
appears to be as good, or even better, than many existing drugs with the
potential to work against a broad range of fatal infections such as pneumonia
and tuberculosis.
Teixobactin has been found to treat many common bacterial
infections such as tuberculosis, septicaemia and C. diff, and could be
available within five years.
But more importantly it could pave the way for a new
generation of antibiotics because of the way it was discovered.
Chemical Structure
Scientists have always believed that the soil was teeming with
new and potent antibiotics because bacteria have developed novel ways to fight
off other microbes.
Laboratory tests have shown the new antibiotic,
called teixobactin, can kill some bacteria as quickly as established
antibiotics and can cure laboratory mice suffering from bacterial infections
with no toxic side-effects.
Studies have
also revealed the prototype drug works against harmful bacteria in a unique way
that is highly unlikely to lead to drug-resistance – one of the biggest
stumbling blocks in developing new antibiotics.
Such a
development would represent a huge boost for medicine because of growing fears
that the world is running out of effective antibiotics given the rapid rise of
drug-resistant strains of superbugs and the spread of these diseases around the
globe.
Last year David
Cameron warned that medicine could be cast back to the “dark ages” when people
died of relatively trivial infections, especially following routine hospital
operations, because of the lack of effective antibiotics.
Professor Kim
Lewis of Northeastern University in Boston – who led the research and is
working with NovoBiotic Pharmaceuticals, based in Cambridge, Massachusetts,
which owns the patents on teixobactin – said that the first clinical trials on
humans could begin in two years and, if successful, the drug could be in
widespread use in 10 years.
“The problem is
that pathogens are acquiring resistance faster than we can develop new
antibiotics and this is causing a human health crisis. We now have some strains
of tuberculosis that are resistant to all available antibiotics,” Professor
Lewis said.
“Teixobactin is
highly effective against tuberculosis and there is an opportunity to develop a
single-drug treatment against tuberculosis based on teixobactin rather than a
treatment regime based on administering three different antibiotics.”
Test-tube
studies, published in the journal Nature, showed that teixobactin was able to
kill bacteria as quickly as the antibiotics vancomycin and oxacillin.
Scientists at
the University of Bonn in Germany have shown that teixobactin works in a unique
way by binding to the fatty lipids that form the building blocks used by bacteria
to manufacture their cell walls.
“This binding
site represents a particular Achilles heel for antibiotic attack and this may
also explain why resistance to teixobactin was not detected,” said Tanya
Schneider of Bonn University.
Professor Lewis
said that the failure to detect any signs of resistance to teixobactin
establishes a new paradigm in the development of antibiotics, which had assumed
resistance will eventually occur.
“Bacteria
develop resistance by mutations in their proteins. The targets of teixobactin
are not proteins, they are polymer precursors of cell wall building blocks so
there is really nothing to mutate,” Professor Lewis said.
“We’ve been
operating under the dogma that the development of resistance is inevitable and
we need to focus on introducing antibiotics faster than pathogens can acquire
resistance,” he said.
“Teixobactin
gives us an example of how we can develop an alternative strategy on developing
compounds where resistance is not going to rapidly develop,” he added.
About 25,000
people a year in Europe alone already die from infections that are resistant to
antibiotics and the World Health Organisation has described the rise of
antibiotic-resistance as one of the most significant global risks facing modern
medicine.
Professor Mark
Woolhouse, Professor of Infectious Disease Epidemiology at the University of
Edinburgh, said: “Any report of a new antibiotic is auspicious, but what most
excites me about [this research] is the tantalising prospect that this
discovery is just the tip of the iceberg... It may be that we will find more,
perhaps many more, antibiotics using these latest techniques. We should
certainly be trying – the antibiotic pipeline has been drying up for many years
now; we need to open it up again, and develop alternatives to antibiotics at
the same time, if we are to avert a public health disaster.”
But Dr Angelika
Gründling, Reader in Molecular Microbiology at Imperial College London, said:
“It’s important to bear in mind that the new antibiotic only works against
certain types of bacteria – such as MRSA and streptococcus, and not on other
multi-drug resistant pathogens such as E. coli... And of course the new
antibiotic described in the paper has yet to be tested in humans. It is
possible that it might not be as effective as hoped and there could be
unforeseen side-effects that might limit its use.”
Mechanism
of action
Teixobactin
is an inhibitor of cell wall synthesis
that acts primarily by binding to lipid II, a fatty
molecule which is a precursor to peptidoglycan. Lipid
II is also targeted by the antibiotic vancomycin. Binding
of teixobactin to lipid precursors inhibits production of the peptidoglycan
layer, leading to lysis of
vulnerable bacteria.
Biosynthesis
and Spectrum
Teixobactin is synthesized in
Eleftheria terrae by nonribosomal peptide synthetases Txo1 and Txo2 (Encoded by
genes txo1 and txo2). It is potent in-vitro against most gram positive bacteria
including S. aureus, Enterococci, M tuberculosis Clostridium difficile,
Bacillus anthracis and also in vivo methicillin-resistant aureus (MRSA),
streptococcal pneumonia.
It also shows good activity against strains of E. Coli
with a defective outer membrane permeability barrier. It is more robust against
mutation of the target pathogens because of its unusual antibiotic mechanism of
binding to less mutable fatty molecules rather than binding to relatively
mutable proteins in the bacterial cell.
Pharmacodynamic
Properties
Teixobactin inhibits bacterial
cell wall synthesis primarily acting by binding to lipid II-precursor to
peptidoglycan and lipid III–precursor of cell wall teichoic acid leading to
lysis of vulnerable bacteria. So there is excellent bactericidal activity. This
is similar to the mechanism of action of Vancomycin.
Teixobactin forms a complex by
binding to lipid I, II,and III by and incubating 2 nmol of each purified
precursor with 2 to 4 n mole of Teixobactin for 30 min at room temperature.
Teixobactin and control compounds like vancomycin/ lassomycin were incubated
with human liver microsome at 37°c to determine their effect on five major
Cytochrome p450s.
Pharmacokinetic
Properties
The mean plasma concentration
of Teixobactin after a single iv injection of 20mg per kg Teixobactin. Few
Pharmacokinetic parameters are highlighted as initial.
Con (27.2ug/ml); AUC to last
(57.8ug-hr/ml); T1/2 (4.7hr) Total Cl (6.9ml/hr); Total Cl (5.8ml/min/kg); Vol.
of distribution (47ml) Vss (9.7ml); Last time point (24hr); Oral route is
preferred than parenteral route.
Adverse drug
events and clinical uses
a) Mammalian cytotoxicity; Haemolytic activity; Complex
formation of Teixobactin.
b) Life
threatening blood and lung infections with staphylococcus aureus and
streptococcus pneumoniae ;infections of heart, prostate, urinary tract and
abdomen with enterococcus; Infections with vancomycin resistance
enterococcus(VRE); infections with MRSA.
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