TEIXOBACTIN

Abstract :Antibiotic resistance is spreading

faster than the introduction of new
compounds into clinical practice,causing a
public health crisis.Most antibiotics were
produced by screening soil
microorganisms,but this limited resources
of cultivable bacteria was overmined by
the 1960s. Synthetic approaches to
produce antibiotics have been unable to
replace this platform. Uncultured bacteria
make up approximately 99% of all species
in external environments, and are an
untapped source of new antibiotics. We
developed several methods to grow
uncultured organisms by cultivation in situ
or by using specific growth factors. Here
we report a new antibiotic that we turn
teixobactin, discovered in a screen of
uncultured bacteria. Teixobactin inhibits

cell wall synthesis by binding to a highly

conserved motif of lipid II (precursor of
peptidoglycan) and lipid III (precursor of
cell wall teichoic acid.) We did not obtain
any mutants of staphylococcus aureus or
mycobacterium tuberculosis resistant to
teixobactin. The properties of this
compound suggest a path towards
developing antibiotics that are likely to
avoid development of resistance.
Formula :- C58H95N15O15
Molecular mass :- 1242.47 g/mol

Teixobactin :Teixobactin is a small molecular

antibiotic that is active against gram-positive
bacteria. It appears to belong to a new class of
antibiotics, and harms bacteria by blinding to
lipid II and lipid III, important precursor
molecules for forming the cell wall. Its
discovery was announced in early 2015 in the
journal nature.

Teixobactin was discovered using a

new method of culturing bacteria in soil, which
allowed researchers to grow a previously
unculturable bacteria now named Eleftheria
terrae, which produces the antibiotic. In the
nature study, teixobactin was shown to kill
Staphylococcus aureus or mycobacterium
tuberculosis whithout the bacteria developing
resistance.

History :Tests for antibacterial activity against

staphylococcus aureus highlighted a previously
undescribed bacterium which was named
Eleftheria terrae. It was found to be producing
a new antibiotic compound that the
researchers named teixobactin. Its absolute
stereochemistry was determined employing
techniques that included chemical degradation
with advanced marfeys analysis as well as
partial degradation, synthesis of fragments
obtained by degradation and the synthesis of
all four occurring in proteins.

Teixobactin is the first novel antibiotic

with drug potential isolated from bacteria in
decades, and appears to represent a new class
of antibiotics, raising hopes that the new
isolation techniques employed could lead to
further antibiotic discoveries.
Biosynthesis :Teixobactin is an 11-residue, macrocyclic
depsipeptide hypothesized by its discoverers to
be synthesized in E.terrae by the nonribosomal
peptide synthetases Txo1 and Txo2(enclosed
by the genes txo1 and txo2). The peptide has
several unusual features, including four Damino acids, a methylated phenylalanine, and
the non-proteinogenic amino acid
enduracididine. Txo1 and Txo2 are together
composed of 11 modules, and each module os
thought to sequentially add one amino acid to
a growing peptides chains. The first module
has a methyltransferase domain that
methylates the N-terminal phenylalanine. Ring
closure between threonine and the last
ioleucine is catalyzed by two C-terminal

thioesterase domains of Txo2, forming a

lactone.
Antibacterial activity :-

1.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. This is similar to the action of the
antibiotic vancomycin. Binding of teixobactin to
lipid precursors inhibits productions of the
peptidoglycan layer, leading to lysis of vulnerable
bacteria.

Activity :Model for the mechanism of action of

teixobactin: lipid II, precursor of peptidoglycan, is
synthesized in the cytoplasm and flipped to the
surface of the inner membrane by MurJ or ftsW;
lipid III, a precursor of wall teichoic acid (WTA), is
similarly formed inside the cell and WTA lipid-

bound precursors are translocated across the

cytoplasmic membrane by the ABC-transporter
TarGH. Teixobactin (TEIX) forms a stoichiometric
complex with cell wall precursor, lipid II and lipid III.
Abduction of these building blocks simultaneously
interrupts peptidpglycan (right), WTA (left)
biosynthesis as well as precursor recycling. Binding
to multiple targets within the cell wall pathways
obstructs the formation of a functional cell
envelope. The producer of Teixobactin os a gram
negative bacterium which is protected from this
compound by exporting it outside of its outer
membrane permeability barrier; the target grampositive organisms do not have an outer
membrane. CM- cytoplasmic membrane; CW- cell
wall; OM- outer membrane; LTA- lipoteichoic acid;
WTA- wall teichoic acid. Image credit: Losee L. Ling
et al.

 Clinical research :In early 2015, human clinical

trials of Teixobactin were estimated to be at least
two years away. One co-doscoverer estimated a
drug development cost in the low 100- millions
on a five to six year schedule. Pharmaceutical
companies have been reluctant to make such
investiments in new antibiotics, because their wide
prescription is likely to be discouraged on order to
retard development of resistance, which has come
to be considered almost inevitable.

 Intellectual property :The research was funded by the

National Institutes of health and german research
agencies ( some co-authors are based at the
University of Bonn). Northeastern University holds
a patent on the iChip method of culturing and
isolating bacteria in situ in soil, and licensed this
patent to a privately held company, Novobiotic
Pharmaceuticals, in Cambridge, Massachusetts,
which owns the patent rights to any compounds
produced. Kim Lewis, the lead author of the article
in Nature, is a founder and paid consultant to this
company.

What did the research involve?

The term designed and tested a number of
methods to grow(culture) previously un-growable
(unculturable) micro-organism.
This including making a device (ichip) that could be
immersed in soil to trick the organisms into
growing, but still allowed the team to isolate the
micro-organisms for further study. This was used

alongside a range of chemical growth factors to

encourage and maintain growth.
When successful, they screened the newly cultures
organisms for any signs that they were producing
antibiotics. A number of new chemicals that lloked
promising were found and then tested in mice,
including mice infected with methicillin-resistant
staphylococcus aureus (MRSA).

Basic results :The results revealed a number of

striking new discoveries :
Researchers could successfully grow a
range of new organisms from the soil,
which had never been done before.
Some of these newly grown organisms
naturally produced antibiotics.
One such antibiotic, named teixobactin,
was particularly promising and was
subsequently syudied intensely in the
laboratory and in mice.
Tests in mice revealed teixobactin was
effective against Gram-positive bacteria
including MRSA and the bacteria that cause
TB. However, it was not effective against

Gram-negative bacteria such as E.coli,

which have an extra layer of cell wall
protection.
Teixobactin inhibited cell wall synthesis via
a mechanism that bacteria are unlikely to
develop resistance to, as it is so
fundamental to their normal survival.
Backing this up, when teixobactin was
used against bacteria Staphylococcus
aureus or Mycobacterium tuberculosis no
drug-resistant bacteria were found or
developed. This is unusual, as most tests
reveal some naturally occurring resistance
over time.

Conclusion:This study shows the discovery

mechanism of teixobactin and is exciting for two
reasons. Teixobactin by itself shows effectiveness
against MRSA and TB in mice models and has
properties indicating that drug resistance may be

unlikely to develop. This is encouraging for the

potential future development of it for human
diseases caused by gram-positive bacteria.
Also, the mechanism of discovery
shows great promise. The research team devised a
completely new way of growing micro-organisms
from soil that could not previously be grown. These
mocro-organisms, 99% of which are unknown to
science, have the potential to produce natural
antibiotics. Therefore, this discovery opens up the
possibility that many more antibiotics cab be found
in the fature. This is encouraging as there has been
a lack of new antibiotic discoveries since the
1980s, while at the same time, the problem of
drug-resistant bacteria has been growing.
While this discovery is undoubtedly
good news there are a number of moderating
factors to bear in mind.

We dont know what proportion of the 99% of

currently ungrowable bacteria this new method
will help to unleash, and what proportion of
them might yield useful antibiotics.
Teixobactin has so far only been trialled in the
lab and in mice. We need to await tests in

humans before we can be sure it works and is

safe.
Teixobactin looks effective against a subset of
bacteria only (Gram-positive bacteria) so is not
a cure-all for bacterial diseases.

With these limitations in mind,

for once a study matches up to the media hype, as
it discovered a promising new antibiotic candidate
(teixobactin) and shows us a method that has the
potential to lead to many more.
It is early days, but we could
potentially be heading into a future where
antibiotic-resistance is a thing of the past.

References : Ab wright Gerard (7 jan.2015). antibiotics:

An irresistible newcomer

 Ab Lewis,Kim (7 jan.2015) novobiotic

reports the discovery of teixobactin, a new
antibiotic without detectable resistance
Cambridge, Massachusetts
Abc Gallagher, james(7 jan.2015)
antibiotics: US discovery labeled gamecharger for medicine.
Abc Denise, Grady ( 7 jan.2015) From a
pile of dirt, hope for a powerful new
antibiotics The New York Times.
Ab Judy Stone (8 jan. 2015) teixobactin
and iChip promise hope against Antibiotic
Resistance.