NEW ANTIBIOTICS
Re-arming
the antibiotic
arsenal
© SCIENCE PHOTO LIBRARY
With drug-resistant bacteria constantly in the news,
what is being done to develop better treatments?
Phillip Broadwith takes a look
48 | Chemistry World | October 2013 | www.chemistryworld.org
NEW ANTIBIOTICS
Teichoic acid
Lipoteichoic acid
Lipopolysaccharide
Outer membrane
Peptidoglycan
Porin
Lipoproteins
Peptidoglycan
Peptidoglycan
© SHUTTERSTOCK
Plasma membrane
Plasma membrane
Membrane proteins
Membrane proteins
Cytoplasm
Modern medicine is facing a significant
threat. Our antibiotics are becoming less
and less effective, and we aren’t developing
new ones nearly fast enough to keep up.
Hardly a few months goes by without
someone foretelling the return to a time when
seemingly minor infections become lifethreatening incidents.
So what is the problem? Why is antibiotic
development progressing so slowly? Put
simply, the research is very difficult, and
the economics are not entirely favourable.
‘When we create a new antibiotic that works
well against resistant pathogens, the world
will say thank you, then put it in reserve until
they absolutely have to use it,’ says David
Payne, head of antibacterial research at
GlaxoSmithKline (GSK). ‘That’s absolutely
appropriate and as it should be, but the return
on investment in that scenario is challenging
for a drug company.’ Antibiotics are as
expensive to develop as other drugs, but if
their use is restricted to small populations for
short treatments, then recouping those costs
is trickier.
GSK is one of the few large pharmaceutical
companies still pursuing antibiotics research,
but Payne admits that his unit makes up a
relatively small part of the company. Instead
of a large in-house research programme, GSK
has turned to public–private partnerships
to share some of the financial and scientific
burdens. As a partner in Europe’s Innovative
Medicines Initiative, the company is working
with academic and industrial collaborators to
address some of the challenges in developing
new drugs against resistant bacteria.
GSK has also joined forces with the US
government’s Biomedical Advanced Research
and Development Authority, which is
providing up to $200 million (£128 million) in
funding over five years. The structure of this
Cytoplasm
Gram negative bacteria
(left) are particularly
hard to kill: compared to
Gram positive (right) they
have more protective
cell walls and a pump to
remove drugs
partnership is as significant as the money, says
Payne. Unlike many other agreements, it is
not focused on a single candidate compound,
but allows resources to be moved between
projects. This means that if one molecule fails
– as often happens in drug development – the
research can continue without renegotiating
the contract.
Target in sight
GSK currently has three antibacterial
compounds in the early stages of clinical trials,
Payne says, each focused on a different route
to beating resistance. One is a new variant of
the well-established cephalosporin family.
The second inhibits type 2 topoisomerase,
which is the enzyme that unwinds DNA as
it is replicated. This is the same target as
existing fluoroquinolone antibiotics, but the
drug binds at a different site. ‘That means
the mutations that make bacteria resistant to
fluoroquinolones
won’t confer the same
‘There’s nothing
resistance against
magical about
these compounds,’
natural products; Payne explains.
The third is
they’re still just
perhaps the most
small molecules’ interesting – it
inhibits polypeptide
deformylase, which is an entirely new
mechanism of action. Payne describes the
hunt for new ways to kill bacteria as ‘one of
the most significant fundamental challenges
we face’. This is particularly true for Gram
negative bacteria, which have extra layers of
protective cell walls that prevent drugs getting
into the cells, and have evolved efflux pump
proteins to push them back out again if they
do manage to penetrate the cell wall.
The hunt for new modes of action is
long and difficult. David Spring from the
University of Cambridge in the UK thinks
that while those factors make it unattractive
to industry, it is an area where academic
researchers can make useful contributions.
Spring argues that one reason why companies
aren’t finding many new drugs is that they’re
looking in the same places all the time. ‘Most
programmes start with a high-throughput
screen of the company’s proprietary
compound library,’ he says. ‘If you look at
those libraries, a lot of people have been
making the same kinds of molecules – there
isn’t a great deal of skeletal diversity.’
Spring also points to the fact that many of
the most successful antibiotics are derived
from natural products – often produced by
other organisms as a defence against infection.
‘There’s nothing magical about natural
products,’ he says; ‘they’re still just small
molecules.’ But what natural product-derived
drugs do tend to have is more 3D complexity:
for example, stereocentres or macrocyclic and
polycyclic scaffolds. ‘We try to make libraries
of skeletally diverse, 3D molecules that are
natural product-like, then we screen them for
antibacterial activity. If there’s even a tiny hint
of activity, you can then start to investigate
and optimise that lead using more traditional
medicinal chemistry.’
www.chemistryworld.org | October 2013 | Chemistry World | 49
NEW ANTIBIOTICS
© DISCUVA
Discuva screens
potential drugs against
mutant strains of
bacteria to understand
how the drug might work
and how resistance may
evolve
One bug, one drug
As a side effect, exploring new areas of
‘chemical space’ like this means that any leads
that emerge are unlikely to look anything like
existing drugs. This makes the intellectual
property around them more valuable and
patents easier to establish and defend. It
also tends to make the molecules more
selective – either for killing bacteria without
harming the patient’s cells, or for killing just
pathogenic bacteria, leaving the ‘good bacteria’
populations on our skin and in our guts intact.
This is the kind of treatment that
Cambridge-based start-up Discuva is aiming
to develop. ‘We’ve become used to using
relatively broad spectrum antibiotics, and
having generic drugs that are very cheap,’ says
Discuva’s chief executive, David Williams. ‘But
the broad spectrum drugs don’t work any more
in Gram negative infections.’ That wipes out
the generics market, and provides an incentive
for developing innovative drugs. ‘This is an
ideal opportunity to redefine the way we treat
microbial infection,’ he says.
Instead of looking for new broad spectrum
drugs, which by their nature will be very
susceptible to resistance, Williams argues we
should be developing more targeted therapies
for specific infections. These could then be
mixed and matched in combinations to help
prevent resistance developing by increasing
the number of hits bacteria have to take to
survive the treatment.
Discuva has developed screening
technology that allows it to elucidate a
potential antibiotic’s mode of action, as well
as any potential resistance mechanisms. It
works by screening an active lead compound
against enormous libraries of mutant strains
of the relevant type of bacteria, with a high
density of mutations spanning the entire
genome. Looking at which of the mutants
survive best gives a picture of what proteins
or pathways are essential for the bacterial
resistance. This indicates what it could
be targeting, but also how easy it is for
resistance to arise from random mutations.
It also identifies proteins that might confer
resistance without being essential to survival,
for example efflux pumps or enzymes that
rapidly break down the compound.
‘Suddenly you can look inside bacteria
and see what’s happening,’ says Williams.
Traditional genetic and biochemical methods
to get the same kind of information would take
years, he adds, whereas
Discuva can get the
‘The drug
same information
discovery
in a few days. The
process generates
pipeline is a
lottery – chances vast quantities of
data, which is then
of success are
unpicked using the
very small’
company’s proprietary
bioinformatics
platform. That
large dataset gives the conclusions a strong
statistical backing, so the company can be sure
that the results are real and reproducible.
Teaching old drugs new tricks
The flip side of using narrow-spectrum,
targeted antibiotics is that you need to know
what bug is causing an infection to know
what drug to use against it. New diagnostic
techniques and equipment are making
50 | Chemistry World | October 2013 | www.chemistryworld.org
headway but, in a chicken-and-egg scenario, it
will be difficult for them to become established
in clinical settings until more drugs that
require such specific diagnoses are available.
One possible way to speed such drugs to
the market is to reinvestigate older drugs that
have fallen out of favour or been abandoned
for some reason. ‘Just because a drug is new,
doesn’t necessarily mean it’s better,’ says
James Harrison, chief executive of Cycle
Pharmaceuticals. Also based in Cambridge,
Cycle aims to improve access to existing
drugs that could be useful but are limited by
factors like a lack of suppliers or unsuitable
formulations.
Reviving existing drugs is much less
risky than trying to discover new ones, both
financially and in terms of patient safety,
says Harrison. ‘The drug discovery pipeline
is a lottery – the chances of success are very
small. Some of the drugs we’re looking at
have years of safety data behind them.’ The
company is working with the US Food and
Drug Administration (FDA) to reinstate some
of these products via short approval pathways.
‘Unlike most English people, we don’t like
waiting in long queues,’ Harrison jokes.
But where do these abandoned drugs come
from? Harrison points out that regulatory
authorities such as the FDA can approve drugs
for marketing, but they can’t force companies
to sell products that they decide are not
worthwhile for some reason. That means that
there are lots of drug files, with all the relevant
safety and clinical trial data, sitting collecting
dust. ‘A small fraction of these are worth
looking at with fresh eyes,’ says Harrison, ‘for
example as adjuvants for antibiotics.’
NEW ANTIBIOTICS
Call off the troops
No matter how many new treatments
we introduce, resistance is an inevitable
consequence of fighting against rapidly
evolving microbes. In the longer term, we need
to understand more about how resistance
arises, and perhaps develop strategies to
negate, or at least slow down, its development.
Spring is investigating one such strategy:
rather than killing the pathogens, they are
trying to deter them from attacking their
hosts. ‘Resistance arises from the evolutionary
pressure to survive in the presence of a drug,’
says Spring. ‘If you allow them to survive, but
essentially stop them from behaving badly, the
evolutionary pressure is quite different.’
Bacteria communicate using small
molecules to allow them to sense how many of
their fellows are nearby. This ‘quorum sensing’
controls a variety of functions, for example
signalling when to coordinate an attack against
the host. Disrupting that communication tips
the balance in favour of the immune system,
allowing it to clear the infection.
This approach could also help make
bacterial populations more susceptible to
antibiotics. Spring explains that in some
diseases, such as cystic fibrosis, bacteria
will form large coordinated networks called
biofilms. These giant ‘bacterial cities’ exude
protective coatings, express different proteins
on their cell surfaces and contain bacterial
cells that are often not dividing very rapidly, so
drugs that target cell wall growth and division
are less effective against them. Breaking down
biofilms, or preventing them from forming
in the first place, would make the pathogens
much more susceptible to antibiotics.
Resisting resistance
As well as how they talk to each other, we still
have a lot to learn about how bacteria interact
with their environment to maintain their
physiological stability, or homeostasis. Stuart
Conway, from the University of Oxford, UK, is
one of many of researchers investigating this
© SCIENCE PHOTO LIBRARY
An adjuvant is given along with the
antibiotic to enhance its activity. That might be
a molecule that helps the drug penetrate the
bacterial cell wall or blocks an efflux pump –
effectively overcoming the bacteria’s defences
and knocking out resistance mechanisms. One
way to identify these synergies is by looking
for examples where researchers or doctors
have tried out combinations successfully, such
as in developing countries where they don’t
have access to newer, more expensive drugs.
Cycle has identified several potential
combination therapies, pairing antibiotics
with drugs that were originally approved as
treatments for other diseases. By focusing
on compounds that are already approved,
the company hopes to bypass some of the
regulatory hurdles faced by new medicines,
and get products onto the market much more
quickly. ‘We are always willing to discuss ideas
of how to expand the use of existing medicines
with researchers or doctors,’ says Harrison.
problem as part of the European Network for
Integrated Cellular Homeostasis. ‘If you can
work out how bacteria maintain homeostasis,
you can potentially work out ways to disrupt it
and kill them, so you can find new targets for
antibiotics,’ Conway says.
Along with collaborators in Aberdeen and
California, Conway’s group is looking at a
particular ion transport channel called Kef.
The channel pumps potassium out of the
cell, while hydrogen ions flow in to balance
the charge. That lowers the interior pH,
which Conway believes helps to protect the
cell by protonating
nucleophilic
‘Resistance
groups on essential
arises from the
biomolecules and
preventing them
evolutionary
from being attacked
pressure to
by electrophilic
survive in the
drugs.
This hypothesis
presence of a
is backed up by the
drug’
fact that the channel
opens in response
to molecular conjugates of glutathione,
which is one of the molecules cells use to mop
up reactive electrophiles and tag them for
transporting out of the cell. ‘It’s conceivable
that this is a kind of synergistic defence
mechanism – if your antibiotic contains an
electrophile, then it will conjugate with
glutathione and be exported from the cell,
but at the same time open up this channel to
drop the pH and protect DNA from alkylation,’
Conway explains.
Biofilms – networks of
bacteria found in diseases
including cystic fibrosis
– are difficult to kill with
drugs that target cell
growth and division
Conway’s research is a long way from
being translated into a functional drug – or
more realistically an adjuvant that could
work alongside other antibiotics to block
this defence pathway. However, the group
has shown that many different glutathione
conjugates will activate the channel, and
has developed fluorescent probes that can
be used to screen for small molecules that
bind to it, which is the first stage in looking
for potential drugs.
Whether or not the newspaper predictions
of a cataclysmic end to the era of antibiotics
come to pass, it is clear that chemists,
microbiologists and medics have their
work cut out. Staying even one step ahead
of the bacterial war machine will require
attack on every front we can muster, from
the immediate firepower of new treatment
options, to longer term gains in learning how
to strategically outmanoeuvre the bugs.
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