Massive breakthrough: Scientists create first new antibiotic in nearly 30 years
LONDON: In a massive breakthrough, scientists have created the first new antibiotic in more than three decades, Teixobactin, that can treat many common bacterial infections such as tuberculosis, septicemia and C Diff or clostridium difficile colitis.
The discovery comes at a time when World Health Organization has sent out warnings that humanity is staring at a post-antibiotic era when common infections will no longer have a cure. The first antibiotic, Penicillin, was discovered by Alexander Fleming in 1928, and more than 100 compounds have been found since then, but no new class has been found since 1987. Antibiotics have been magic bullets for human health for decades but irrational use has made most bugs resistant to these. Northeastern University's professor Kim Lewis announced Thursday the discovery of the antibiotic that eliminates pathogens without encountering any detectable resistance. Lewis and Northeastern biology professor Slava Epstein coauthored the finding with colleagues from the University of Bonn in Germany, Novo Biotic Pharmaceuticals in Cambridge, Massachusetts, and Selcia Ltd in the United Kingdom. Most antibiotics target bacterial proteins, but bugs can become resistant by evolving new kinds of proteins. What's unique about Teixobactin is that it launches a double attack on the building blocks of bacterial cell walls. Experts say this will pave the way for a new generation of antibiotics because of the way it was discovered. Teixobactin could be available in the next five years. Its testing on mice has shown it clears infections without side-effects. The NU team led by Prof Lewis is now concentrating on upscaling production of Teixobactin to test it on humans. Northeastern researchers' pioneering work to develop a novel method for growing uncultured bacteria led to the discovery of the antibiotic, and Lewis's lab played a key role in analyzing and testing the compound for resistance from pathogens. Lewis said this marks the first discovery of an antibiotic to which resistance by mutations of pathogens have not been identified. "So far, the strategy has been based on developing new antibiotics faster than the pathogens acquire resistance. Teixobactin presents a new opportunity to develop compounds that are essentially free of resistance," Lewis said. The screening of soil micro-organisms has produced most antibiotics, but only one per cent of these will grow in the lab, Lewis explained. He and Epstein spent years seeking to address this problem by tapping into a new source of antibiotics beyond those created by synthetic means: uncultured bacteria, which make up 99% of all species in external environments. They developed a novel method for growing uncultured bacteria in their natural environment. Their approach involves the iChip, a miniature device Epstein's team created that can isolate and help grow single cells in their natural environment and provide researchers with much improved access to uncultured bacteria. "Novo Biotic has assembled about 50,000 strains of uncultured bacteria and discovered 25 new antibiotics, of which Teixobactin is the latest and most interesting," Lewis said. "Our impression is that nature produced a compound that evolved to be free of resistance," Lewis said. "This challenges the dogma that we've operated under that bacteria will always develop resistance. Well, maybe not in this case." Britain's chief medical officer, Dame Sally Davies, recently said antibiotic resistant was "as big a risk as terrorism", and warned that Britain faced returning to 19th century scourges when the smallest infection or operations could kill. WHO said a comprehensive study of antibiotic development, covering innovative, small firms, as well as pharmaceutical giants found that only 15 out of 167 antibiotics under development had a new mechanism of action with the potential to meet the challenge of multidrug resistance.
Reff:http://timesofindia.indiatimes.com/home/science/Massive-breakthrough-Scientists-create-first-new-antibiotic-in-nearly-30-years/articleshow/45807598.cms
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Superbugs threaten a return to the ‘dark ages’
Britain will lead the fightback against antibiotic-resistant
superbugs threatening to send medicine "back into the dark ages", David
Cameron has said. |
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The Prime Minister said resistance to antibiotics was a "very real
and worrying threat" and could lead to a future in which currently
treatable injuries and ailments could prove fatal.
As part of the effort to address the issue an international group of
experts will aim to stimulate the development of a "new generation of
antibiotics", The Times reported.
"This is not some distant threat but something happening right now,"
Mr Cameron told the newspaper. "If we fail we are looking at an almost
unthinkable scenario where antibiotics no longer work and we are cast
back into the dark ages of medicine where treatable infections and
injuries will kill once again.
"That simply cannot be allowed to happen and I want to see a stronger, more coherent global response."
Former Goldman Sachs chief economist Jim O'Neill will lead the
international expert group and has been asked to consider how
governments would pay pharmaceutical companies to produce drugs even if
they were rarely used.
The group will also consider how poorer countries can be encouraged to improve control of existing antibiotics.
The Prime Minister told The Times: " I've been listening to the
scientific advice that I get, and the network of advisers we have are
all saying this is one of the most serious health problems the world
faces.
"For many of us we only know a world where infections or sicknesses
can be quickly remedied by a visit to the doctor and a course of
antibiotics.
"This great British discovery has kept our families safe for decades, while saving billions of lives around the world.
"But that protection is at risk as never before. Resistance to antibiotics is now a very real and worrying threat."
He added: "When we've had these problems in the past, whether it
is how we tackle HIV and Aids, how it is possible to lead the world
and get rid of diseases like polio, Britain has taken a lead and I
think it is right we take a lead again."
The Prime Minister raised the issue privately with US president
Barack Obama and German chancellor Angela Merkel during the G7 summit
last month.
The initial £500,000 cost of the work will be met by the Wellcome
Trust, whose director Jeremy Farrar said: "Drug-resistant bacteria,
viruses and parasites are driving a global health crisis.
"It threatens not only our ability to treat deadly infections, but
almost every aspect of modern medicine: from cancer treatment to
Caesarean sections, therapies that save thousands of lives every day
rely on antibiotics that could soon be lost.
"We are failing to contain the rise of resistance, and failing to
develop new drugs to replace those that no longer work. We are heading
for a post-antibiotic age.
"This is not just a scientific and medical challenge, but an economic
and social one too. I am thus delighted that an economist of the
stature of Jim O'Neill has agreed to investigate these issues, with an
eye on the incentives, regulatory systems and behavioural changes that
will be required to resolve them.
"The Wellcome Trust is proud to fund and host Jim and his team as they conduct this vital work.
"Drug-resistant infection is one of the most urgent challenges of our
time. It demands the attention of world leaders and international
action, which is why it is encouraging that David Cameron is taking the
issue so seriously and giving it the profile it deserves."
Professor Dame Sally Davies, the chief medical officer for England,
said: "We must act now on a global scale to slow down antimicrobial
resistance.
"In Europe, at least 25,000 people a year already die from
infections which are resistant to our drugs of last resort. New
antibiotics made by the biotech and pharmaceutical industry will be
central to resolving this crisis which will impact on all areas of
modern medicine.
"I am delighted to see the Prime Minister taking a global lead by
commissioning this review to help new antibiotics to be developed and
brought to patients effectively."
The world could soon be "cast back into the dark
ages of medicine" unless action is taken to tackle the growing threat
of resistance to antibiotics, Prime Minister David Cameron has said.
He has announced a review into why so few anti-microbial drugs have been introduced in recent years.
Economist Jim O'Neill will lead a panel including experts from science, finance, industry, and global health.
It will set out plans for encouraging the development of new antibiotics.
'Taking the lead'
The prime minister said: "If we fail to act, we are looking at
an almost unthinkable scenario where antibiotics no longer work and we
are cast back into the dark ages of medicine where treatable infections
and injuries will kill once again."
Mr Cameron said he discussed the issue at a G7 leaders
meeting in Brussels earlier this month and got specific support from US
President Barack Obama and German Chancellor Angela Merkel.
It is hoped that the review panel's proposals will be discussed at next year's G7 summit, which will be hosted by Germany.
"Penicillin was a great British invention by Alexander
Fleming back in 1928," Mr Cameron told the BBC. "It's good that Britain
is taking the lead on this issue to solve what could otherwise be a
really serious global health problem."
He said the panel would analyse three key issues: the
increase in drug-resistant strains of bacteria, the "market failure"
which has seen
no new classes of antibiotics for more than 25 years, and the over-use of antibiotics globally.
'Time bomb'
It is estimated that drug-resistant strains of bacteria are
responsible for 5,000 deaths a year in the UK and 25,000 deaths a year
in Europe.
A resistant strain of bacteria
Chief Medical Officer for England Prof Dame Sally Davies has
been a key figure helping to get the issue on the government and global
agenda.
Last year she described the threat of antimicrobial
resistance as a "ticking time bomb" and said the dangers it posed should
be ranked along with terrorism.
She spoke at a meeting of scientists at the Royal Society
last month which warned that a response was needed akin to efforts to
combat climate change.
Dame Sally said: "I am delighted to see the prime minister taking a global lead by commissioning this review.
"New antibiotics made by the biotech and pharmaceutical
industry will be central to resolving this crisis which will impact on
all areas of modern medicine."
Medical research charity the Wellcome Trust is providing
£500,000 of funding for Mr O'Neill and his team, which will be based at
their headquarters in central London.
Antimicrobial resistance has been a key issue for Jeremy Farrar, since he became director of the Wellcome Trust last year.
"Drug-resistant bacteria, viruses and parasites are driving a global health crisis," he said.
"It threatens not only our ability to treat deadly
infections, but almost every aspect of modern medicine: from cancer
treatment to Caesarean sections, therapies that save thousands of lives
every day rely on antibiotics that could soon be lost."
'Market failure'
Antibiotics have been an incredible success story, but bacteria eventually develop resistance through mutation.
One example is MRSA, which has been a major threat for years
in hospitals. It is resistant to all but the most powerful of
antibiotics, and the main weapon against it is improved hygiene, which
cuts the opportunity for infection to spread.
Without antibiotics a whole raft of surgical procedures would
be imperilled, from hip replacements to cancer chemotherapy and organ
transplants.
Before antibiotics, many women died after childbirth after developing a simple bacterial infection.
Mr O'Neill is a high-profile economist who is best-known for
coining the terms Bric and Mint - acronyms to describe countries which
are emerging and potential powerhouses of the world economy.
He is not, though an expert on antibiotics or microbes. But
Mr Cameron told the BBC it was important to have an economist heading
the review:
"There is a market failure; the pharmaceutical industry
hasn't been developing new classes of antibiotics, so we need to create
incentives."
Jeremy Farrar said: "This is not just a scientific and
medical challenge, but an economic and social one too which would
require analysis of regulatory systems and behavioural changes to solve
them."
Mr O'Neill will begin work in September and is expected to deliver his recommendations next spring.
Last month antibiotic resistance was selected as the focus
for the £10m Longitude Prize, set up to tackle a major challenge of our
time.
http://www.guardian-series.co.uk/uk_national_news/11313176.UK_to_lead_superbug_fight___Cameron/
Reff: The Times of London-Twitter, http://www.bbc.com/news/health-28098838
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How a Microbe Resists Its Own Antibiotics
Researchers reveal the molecular mechanisms of Streptomyces platensis’s defense from its own antibiotics, which inhibit fatty acid synthesis in other microbes.
“It is a nice piece of work and is perhaps one of the first complete
demonstrations of antibiotic resistance mechanisms from genome
sequencing information,” microbiologist
Julian Davies, a professor emeritus at the University of British Columbia who was not involved in the work, told
The Scientist in an e-mail.
“The novelty is in the detail here,” agreed
David Hopwood,
former head of the genetics department and now emeritus fellow at the
John Innes Centre, who also did not participate in the research. “It
tells us a lot of interesting things about fatty acid biosynthesis in
bacteria . . . [and] about the way that the antibiotics interact with
[that] pathway.”
Since researchers first identified platensimycin and platencin, they
have questioned how the compounds do not disrupt the synthesis of
S. platensis’s
own fatty acids. “If the organism is making an antibiotic which is
potentially lethal, it has to protect itself,” Hopwood said. “So almost
always an antibiotic producer has self-protecting mechanisms.”
To identify those mechanisms, Scripps microbiologist
Ben Shen and his colleagues performed bioinformatics analyses of the open reading frames in the genomes of two strains of
S. platensis
and identified four genes that, based on their homology to enzymes of
known function and their apparent lack of a role in antibiotic
biosynthesis, the researchers hypothesized may confer resistance to
platensimycin and platencin. Follow-up experiments revealed that the
enzyme PtmP3, which is resistant to the antibiotics, had replaced two
fatty acid biosynthesis enzymes, FabF and FabH, which are normally
inhibited by the compounds, and expression of PtmP3 in the normally
susceptible
S. albus rendered the bacteria resistant to both antibiotics. Moreover,
S. platensis’s
FabF had evolved structural changes so as to be resistant to
platensimycin, serving as “a second form of self-resistance,” the
authors wrote.
Similar self-resistance mechanisms were previously identified in other bacteria—for example, in
Pantoea agglomerans,
which produces the antimicrobial compound andrimid. “The way the
producing bacterium copes with this dilemma is to make its own enzyme
resistant to the inhibitor,” microbiologist and biochemist
John Cronan
at the University of Illinois at Urbana-Champaign, who was not involved
in the work, wrote in an e-mail. “[T]his is essentially the same
message that the Shen paper reports.”
Whether the findings could inform platensimycin and platencin
development efforts remains to be seen, however. “[B]oth compounds have
poor pharmacokinetics,” Cronan noted. “They have too high a rate of
clearance in the body and gram negative bacteria are resistant due to
efflux pumps. . . . As far as the future of these compounds my guess is
that they will fail (or have already failed).”
Nevertheless, Shen and his colleagues are hopeful that understanding how
S. platensis protects itself will yield insight that could aid the development of platensimycin and platencin.
“Development of resistance in pathogenic bacteria has widely been
attributed to horizontal gene transfer from nonpathogenic bacteria with
one potential source being antibiotic-producing bacteria that developed
highly effective mechanisms to avoid suicide,” the authors wrote in
their paper. “Understanding self-resistance mechanisms within
[platensimycin] and [platencin] producing organisms therefore is
imperative for predicting, determining, and thereby managing, potential
resistance that could develop with any future use of [these drugs] or
their derivatives in the clinic.”
R.M. Peterson et al., “Mechanisms of self-resistance in the
platensimycin and platencin producing Streptomyces platensis MA7327 and
MA7339 strains,” Chemistry & Biology, 2014.
Reff.:The.Scientist.com
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Early Evidence
Fossilized structures suggest that mat-forming microbes have been around for almost 3.5 billion years.
OLD
MICROBES: These chips in the rocks of Western Australia’s Dresser
Formation are thought to have been made by ancient microbial mats.COURTESY NORA NOFFKE
EDITOR'S CHOICE IN EVOLUTION/GEOBIOLOGY
The paper
N. Noffke et al., “Microbially induced sedimentary structures recording
an ancient ecosystem in the ca. 3.48 billion-year-old Dresser
Formation, Pilbara, Western Australia,”
Astrobiology, 13:1103-24, 2013.
The background
Modern microorganisms leave traces on substrates called microbially
induced sedimentary structures (MISS)—textures that arise from a biofilm
or microbial mat interacting with the dynamics of the sediments upon
which it forms. Until recently, the oldest fossilized MISS, located in
South Africa, dated back to 3.2 billion years ago. However, evidence
from microfossils and stromatolites, another rock structure shaped by
bacteria, suggests that microbes existed at least 200 million years
earlier.
The evidence
In the Dresser Formation in Western Australia—one of the only places in
the world with well-preserved 3.48-billion-year-old rocks—Nora Noffke
of Old Dominion University in Norfolk, Virginia, and colleagues recorded
microtextures characteristic of biofilms and microbial mats and
uncovered geochemical signals consistent with a biological origin. The
morphology and distribution of the fossils in this ancient coastal salt
flat strongly resembled modern MISS.
The significance
The finding “supports interpretations that life had evolved before 3.4
billion years [ago], as indicated by the presence of both stromatolites
and microfossils,” Kath Grey, who is the former chief paleontologist of
the Geological Survey of Western Australia and was not involved in the
research, wrote in an e-mail to
The Scientist. According to
Noffke, the fossilized MISS’s similarities to contemporary MISS suggest
that ancient biofilms behaved in the same way that modern microbes do.
The origins
The Mars rover is currently hunting for MISS as a sign of life. Here on
Earth, the origin of life predates the fossils from the Dresser
Formation. Even 3.5 billion years ago, “life is already so complex,”
Noffke says. “Its evolution must have taken a lot of time.”
Reff: The.Scientist.com
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Outwitting the Perfect Pathogen
WORLDWIDE
PATHOGEN: About one-third of the human population is infected with
Mycobacterium tuberculosis (cultures shown above), some 13 million of
which are actually sick with TB.CDC/GEORGE KUBICA
In 2009, an international consortium of
researchers initiated an efficacy trial for a new tuberculosis (TB)
vaccine—the first in more than 80 years. With high hopes, a team led by
the South African Tuberculosis Vaccine Initiative inoculated 2,797
infants in the country, half with a vaccine called MVA85A and half with a
placebo. They followed the children for up to three years and finally
announced the result last February. It was not good news (
Lancet, 381:1021-28, 2013).
“It did not work,” says Thomas Evans, president and CEO of Aeras, the
Rockville, Maryland-based nonprofit that sponsored the trial. The
vaccine did not protect children against the deadly disease.
“The whole field was disappointed,” says Robert Ryall, TB vaccine
project leader at Sanofi Pasteur, who was not involved in the trial.
“And unfortunately the field did not learn much.” The vaccine developers
still do not know why MVA85A didn’t work.
The only vaccine currently available in the fight against TB is Bacille
Calmette-Guérin (BCG), a live vaccine first used in 1921 and originally
derived from a cow tuberculosis strain. Though the exact mechanism of
the vaccine’s protection remains unclear, researchers do know that it
doesn’t work well: it reduces the risk of a form of TB that is
especially lethal to infants, but it does not reliably protect against
TB lung infections, which kill more than a million adults worldwide each
year.
With every cough or sneeze of an infected individual, TB bacilli fly
through the air, and to date have spread to one-third of the world’s
population. In most individuals, Mycobacterium tuberculosis (Mtb)
lie dormant, never causing sickness. In others, however, the bacteria
cause life-threatening lung infections. Some 13 million people around
the world are actively sick with TB, and someone dies of the disease
approximately every 20 seconds, according to the World Health
Organization (WHO).
“The need for a TB vaccine is enormous,” says David Sherman, a
tuberculosis expert at the nonprofit Seattle Biomedical Research
Institute. And an inadequate vaccine is not the field’s only problem:
the four main drugs currently used to treat tuberculosis are also
decades old, take six months to rid the body of the bacilli, and are
becoming obsolete due to the spread of multidrug-resistant and
extensively drug-resistant TB. Despite the gloomy outlook, many
researchers are still plugging away, through pharmaceutical-nonprofit
partnerships and redesigned basic research efforts, to achieve a happy
ending.
Ancient foe
BATTLING
TB: Paula Fujiwara (left) of the International Union Against
Tuberculosis and Lung Disease speaks with a woman who is serving as the
treatment supervisor of her 25-month-old child with TB.WHO/TBP/GARY HAMPTONTuberculosis
has plagued humans for thousands of years. Even ancient Egyptians were
ravaged by TB, as evidence from mummies has shown. And over those
millennia,
Mtb has learned to quietly, carefully live within the human body.
“It’s not just a pathogen; in some ways it’s commensal,” says Evans.
“It’s been dealing with the human immune system for a long period of
time and knows how to go latent and keep itself transmitted.” Of the
roughly 2 billion people infected with Mtb, about 90 percent will never
get sick, though they are a vast reservoir of the bacteria, fueling the
epidemic. And when illness occurs, unlike many infections that involve
an acute sickness as the host’s immune system battles the pathogen,
tuberculosis infection resembles a chronic disease. “Everything about
the infection is slowed down, frankly, in ways we don’t understand,”
says Sherman.
E. coli, for example, replicates so quickly—about once every 20 minutes—that one cell can grow into a colony of a million overnight. Mtb,
on the other hand, only doubles once every 20 hours, and would take
three weeks to grow a colony of similar size. Additionally, the human
immune system produces antibodies against most pathogens in roughly 5 to
7 days. Antibody production against Mtb takes three weeks,
likely because the bacteria are slow to travel to the lymph nodes where
an adaptive immune response commences. “TB is exquisitely adapted to
long-term survival in a human host,” says Sherman.
The current TB drug regimen relies on a six-month treatment of four
antibiotics, all discovered in the 1950s and ’60s and which primarily
inhibit cell-wall and RNA synthesis. (See illustration.) Worldwide,
about 3.6 percent of new TB cases and 20 percent of recurring infections
are multidrug resistant, according to the WHO.
Mtb is not just a pathogen; in some ways it’s commensal.
—Thomas Evans, Aeras
Unfortunately, there isn’t a deep pipeline of drug candidates to fall
back on. It wasn’t until December 2012, some 50 years after the last
first-in-class approvals, that the US Food and Drug Administration
approved a TB drug with a new mechanism of action. Janssen Therapeutics’
bedaquiline (Sirturo) inhibits an ATP synthase enzyme in the
bacterium’s cell membrane to prevent the pathogen from generating energy
and replicating. (See illustration.) No other anti-TB drugs are close
to approval.
TB drug development has been slow for several reasons. For one, the
drugs are difficult and expensive to make, and they are primarily needed
in developing countries that can’t afford to pay top dollar for a
six-month drug regimen. “Working in TB will not drive profit for
pharmaceutical companies,” says Manos Perros, head of AstraZeneca’s
Boston-based Infection Innovative Medicines Unit. As a result, most
recent TB drug development has involved collaborations between big
pharma and government institutions or nonprofit advocacy organizations,
as well as academia. These are “partnerships that bring resources and
funding that make this kind of work, frankly, possible,” says Perros.
“This is a space where competitions between pharma and academia are
unfruitful.”
Other pharma companies share that sentiment. In February 2013,
Glaxo-SmithKline (GSK) opened up the closely guarded doors of their
laboratories to share information with the TB research community about
177 compounds from the company’s pharmaceutical library that appear to
inhibit
Mtb (
ChemMedChem,
8:313-21, 2013). The set of compounds has already been sent to nine
groups in the U.K., U.S., Canada, The Netherlands, France, Australia,
Argentina, and India, according to GSK spokesperson Melinda Stubbee.
But even with this collaborative attitude, the research community has
struggled to develop successful new TB drugs, in part because the
bacterium hides latent inside cells such as macrophages, and
unpredictably becomes active in different sites in the lung. “TB drug
development is extremely challenging because a drug has to kill not only
the replicating but the nonreplicating bacteria,” says Feng Wang of the
California Institute for Biomedical Research in La Jolla. To tackle
this problem, Wang, along with Peter Schultz at Scripps Research
Institute, also in La Jolla, and William Jacobs at Albert Einstein
College of Medicine in New York, used a novel screening method to test
the effect of 70,000 compounds on a biofilm of Mtb that simulates the
latent version of the bacterium. One compound popped out of the screen:
TCA1 killed both replicating and nonreplicating
Mtb (
PNAS,
110:E2510-17, 2013). It appeared to attack on two fronts: preventing
bacterial cell-wall synthesis and inhibiting a bacterial enzyme involved
in cofactor biosynthesis, which is likely what makes it effective
against nonreplicating
Mtb. (See illustration.) The compound
has since proven successful in both acute and chronic animal models of
TB, and the team is tweaking the chemistry to try and make it even more
potent, says Wang.
Pharmaceutical company AstraZeneca is similarly developing a drug that
is active against latent bacteria. AZD5847, a type of antibiotic called
an oxazolidinone that is typically used to treat staph infections, is
able to reach and kill Mtb lodging inside macrophages. The
company is currently testing the drug in a Phase 2 efficacy trial in
South Africa involving 75 patients. But developing the compound wasn’t
easy, notes Perros. “We’ve been investing for a decade. It really takes a
long time.”
Seeking a boost
THWARTING
TB: The traditional regimen for TB includes four antibiotics that
primarily inhibit cell-wall synthesis and RNA synthesis. Now,
researchers are looking for new ways to stop the bacterium.
See full infographic: JPG | PDFCDC/RAY BUTLER; ILLUSTRATION BY THE SCIENTIST STAFF; BASED ON NIAID/WIKIMEDIA COMMONSBut even if quick-acting, potent drugs were available,
Mtb
is so abundant and so well adapted to the human population that the
only true path to eradication is not treatment, but prevention. “There’s
no endgame without a vaccine,” says Aeras’s Evans. “No matter how much
we think we should work on drugs or diagnostics, if we’re not working on
vaccines, we’ll never get to our final goal.”
The failure of the MVA85A vaccine trial in South Africa last year was
disappointing, but at least a dozen other TB vaccine candidates continue
in clinical trials. Most of these reflect one of two general strategies
for preventing tuberculosis: improve the existing BCG vaccine or, more
commonly, boost its effect with a secondary vaccine. BCG, which is given
to infants, primes the immune response early in life, so booster
vaccines are usually designed to protect adolescents and adults from
later infection. The MVA85A vaccine, for example, was a modified viral
vector expressing Mtb antigen 85A designed as a booster to BCG.
Vaccine development, however, is hindered by lack of cellular or
molecular markers that directly correlate with immune protection from
TB, making it difficult to predict how well a vaccine might protect
against TB based on the responses of a handful of individuals. “The only
tool we have to make sure a vaccine works is a very large, very
expensive field trial,” says Evans. And that high price tag, as in TB
drug development, has turned numerous pharmaceutical companies off the
pursuit of a TB vaccine.
But with financial and research support from nonprofit partners like
Aeras—funded by the Bill & Melinda Gates Foundation, among others—a
few companies are still in the game. In collaboration with Aeras, Sanofi
Pasteur is developing a BCG booster vaccine that began Phase 1/2a
safety trials in South Africa last July. It is a recombinant vaccine
made up of two TB proteins fused together and coupled with an adjuvant
called IC31, which really “drives the immune response,” says Sanofi’s
Ryall. Aeras also has another big-pharma partnership with GSK on a
vaccine called M72/AS01e, which has been in Phase 1 and 2 clinical
trials since 2004, including an ongoing trial in Taiwan and Estonia. The
vaccine combines a GSK recombinant antigen called M72, derived from two
tuberculosis-expressed proteins, and a GSK adjuvant called AS01e.
Fresh start
BLASTING
TB: An Aeras employee works on the spray dryer, which creates TB
vaccines in a powder form that can be delivered directly to the lungs.AERASWith
TB drugs and vaccines still in early clinical phases, some scientists
are going back to the basics to see if a better molecular understanding
of the bacterium itself could assist these programs. “We need to develop
vaccines, and we need to develop products, but as we do, it’s very
clear that we need to be learning a lot more about the immunobiology [of
TB],” says Evans.
Last July, for example, Sherman and colleagues published the first
large-scale map of the bacterium’s regulatory and metabolic networks (
Nature,
499:178-83, 2013). The team initially plotted the relationships of 50
Mtb transcription factors, and later, all 200, which control the
expression of the rest of the bacterium’s genes. “Our hope is that by
looking at it in this different way, we can describe different kinds of
drug targets than we have ever done before,” says Sherman.
The team found that Mtb is remarkably well networked, so that
if a mutation or drug stymies one gene or protein, others step in as
backups, allowing the bacterium to continue functioning normally. But
targeting transcription factors that control whole networks could shut
down an entire system, backups and all. One such network already looks
like a promising drug target—transcription factors controlling a group
of proteins in the bacterium’s cell membrane that pump antibiotics and
other drugs out of the cell. Mtb has so many such pumps that it is
extremely difficult to target multiple pumps for treatment, but genes
that activate numerous pumps at the same time are a far more promising
drug target.
The idea that scientists will soon develop new, better TB drugs and
vaccines “helps get me up in the morning,” says Sherman. It’s going to
take more breakthroughs than are on the immediate horizon, he adds, “but
if we keep at it, we will get there.”
Reff:http://www.the-scientist.com/?articles.view/articleNo/38708/title/Outwitting-the-Perfect-Pathogen/
