As a global debate rages on the
future of antibiotics due to the presence of yet another “super
bug”, NDM-1 resisting all known antibiotic treatments, the health
community is seriously looking at alternate options
One of the most promising alternative appears to be the
use of bacteriophages, the viruses that kill bacteria, which was used
extensively in many parts of the world prior to the discovery of the
wonder antibiotic pencillin in the 1920s. The super convenience of
penicillin and other antibiotics relegated phages to the background.
GangaGen Biotechnologies, founded by a renowned molecular biologist
from AstraZeneca 10 years ago to relentlessly pursue phage research, is
close to getting the world's first phage-based product ready to tame
the deadly bacteria strains stalking patients worldwide. GangaGen is
ready to start the human trials of the world's first “superbug” killer,
StaphTAME, a genetically-modified protein developed from phages.
StaphTAME, a novel biological drug, using a genetically-modified
protein, developed from bacteriophages (the viruses that kill bacteria)
by a small Bangalore-based biotech company, GangaGen Biotechnologies,
is all set for human clinical trials in India and the US.
“StaphTAME is a recombinant protein that kills the superbug MRSA
(Methicillin Resistant Staphylococcus Aureaus) and all staph bacteria
rapidly in minutes by a novel mechanism,” disclosed GangaGen founder
and well-known molecular biologist, Dr Janakiraman Ramachandran, who
has been toiling in the labs for the last decade after retiring as the
head of its R&D at AstraZeneca in Bangalore. GangaGen was founded
in 2000 with a `9.36 crore ($2 mn) funding from ICF Ventures.
MRSA is currently the most serious hospital-acquired infection and as
it does not respond to treatments with almost all the known and most
powerful antibiotics, it has been termed a “superbug” out of human
control. In fact, because of the untamed nature of the “superbug,”
experts have been predicting that the era of antibiotics is over. An
alternate method to control harmful bacteria is urgently required. The
New Delhi metallo-beta-lactamase (NDM-1) “superbug” now a cause of
concern in the global medical fraternity is one of MRSA strains.
StaphTAME is the world's first therapeutic protein developed from
bacteriophages to reach the human clinical trials stage. So far,
bacteriophage therapy has been used only for treatments after the
bacterial infections sets in. “All preclinical development of StaphTAME
has been completed and a successful pre-IND meeting with the US
regulator, Food and Drug Administration (FDA) has been concluded,” Dr
Ramachandran shared from the US, as he is preparing for the product's
clinical trials in the US and in India.
StaphTAME, also called the P128 protein, was developed by researchers
at GangaGen's Bangalore (India) and Ottawa (Canada) facilities, based
on a key protein from bacteriophage. When the phage, the virus that
kills bacteria, first interacts with a bacterial cell, they damage the
cell wall in order to insert their genetic material.
“GangaGen has identified the active portion of the phage molecule that
causes this damage, and coupled it with another protein sequence that
allows binding to the surface of Staphylococcus,” explained Dr Bharati
Sriram, a senior researcher at GangaGen. GangaGen has already filed
both composition of matter and use patents for StaphTAME and is now
vigorously pursuing worldwide patent protection for the product.
The P128 protein has been tested against over 200 global strains of S.
aureus, more than half of which are methicillin-resistant, and has
proved capable of killing all of them, revealed Dr Bharati. Some of the
strains used include a panel of 30 New York/New Jersey strains
representing 3,000 isolates, 56 Japanese isolates, 119 Indian isolates
and eight Canadian isolates.
But is this “wonder drug” going to be available soon? For this to
happen, the fledgling startup urgently needs funds to speed up the
clinical trials. Few million dollars are required to conclude the
trials faster. “The main hurdle is lack of adequate financing to
complete the clinical trials quickly,” Dr Ramachandran confessed.
GangaGen, after the meeting with the USFDA in March 2010, has prepared
StaphTAME formulation for intra-nasal use. The company has also scaled
up manufacturing efforts to support clinical studies. The phase I &
II studies will include safety, dosing, and preliminary efficacy
GangaGen is clearly the world leader in developing such a “superbug”
killer product from phages. Exponential Therapies, which has been
developing a similar product since 1994 closed the research program in
2005. Another US-based company, Phage Therapeutics in Seattle,
Washington, too had started to develop a product against MRSA in 1997
but wound up in 2003.
be the “antibiotics killer”?
About 82 years ago, Alexander Fleming discovered antibiotics and
penicillin became a wonder drug in the next few decades. In the six
decades following, medical researchers have developed a wide range of
antibiotics that treat several infectious diseases. However, in the
last two decades, scientists and commentators have started to write
premature obituaries of antibiotics. In fact, the latest headlines in
newspapers based on the NMD-1 reports have a common theme: “Is it the
end of antibiotics?”
But is it really so?
What is happening today seems to be an exact replica of the events more
than 16 years ago. In March 1994, the venerable Newsweek magazine ran a
report, “The End of Antibiotics?” by Sharon Begley. The reference was
to the discussions at the annual meeting of the Association of
Advancement of Science in San Francisco that concluded in February
1994. Microbiologist Alexander Tomasz of Rockefeller University warned,
“many common bacteria are evolving resistance to more and more
The data for 1992 indicated that resistant infections killed 19,000
patients in hospitals in the US that year and contributed to the death
of 58,000 more outside. In 2005, more than two million people in the US
were affected by infections and 90,000 of them died. In the UK, there
were 3,00,000 infected patients with 5,000 deaths, according to
information compiled by science writer, Thomas Hausler in his book,
'Viruses vs Superbugs'.
Even after 16 years, antibiotics continue to thrive even though more
resistance has been reported regularly. Will the August 2010 obituary
on antibiotics also be another such premature exercise?
Majority of the hospital infections are caused by the Staphylococcus
aureus bacteria. Dr Tomasz has found that 70 percent of the known 3,000
strains of this bacteria found all over the world belonged to just five
strains. What this means is that it doesn't matter where the bacteria
was found first. These tiny microbes have always had a way in
spreading themselves to all parts of our planet. So blaming a
particular city, hospital, or country does not help the cause of
finding a quick cure.
Phage therapy i.e., using viruses that kill harmful bacteria, one of
the most promising cures around the corner.
It is certainly not the end of antibiotics. And NMD-1 will not be the
“antibiotics killer” anyway.
Narayanan Suresh and Jahanara Parveen"GangaGen's StaphTAME is ready to tame superbugs"
therapy is not already a treatment of choice?
In order to use phage as a therapy, the pathogen causing the infection
must be properly diagnosed so that the appropriate phage can be used.
Phages are highly specific and a given phage such as the cholera phage
will kill only cholera bacteria but not others. Diagnosis is
difficult. When Penicillin was discovered in the 1930s, physicians in
the Western world abandoned phage and embraced antibiotics since they
had broad spectrum activity. Penicillin could be used to treat many
infections. In fact, it is the overuse and misuse of antibiotics
the last six decades that led to the emergence of robust
antibiotic-resistant pathogens like MRSA. The second major reason why
pharma companies did not pursue phage therapy is the perceived lack of
patent protection, for naturally occurring phages.
As a global debate rages on the future of antibiotics due
to the presence of yet another 'superbug', NDM-1, resisting all known
antibiotic treatments, the health community is seriously looking at
alternate options. One of the most promising alternative, appears to be
the use of bacteriophages-the viruses that kill bacteria-which was used
extensively in many parts of the world, prior to the discovery of the
wonder antibiotic, penicillin, in the 1920s. The super convenience of
penicillin and other antibiotics, relegated phages to the background.
In this gloomy scenario, there is hope.
GangaGen Biotechnologies, founded by a renowned molecular biologist
from AstraZeneca 10 years ago, to relentlessly pursue phage research,
is close to getting the world's first phage-based product ready to tame
the deadly bacteria strains stalking patients around the world.
GangaGen is ready to start the human trials of the world's first
'superbug' killer, StaphTAME, a genetically-modified protein developed
In an exclusive interview to Narayanan Suresh and Jahanara Parveen of
BioSpectrum, GangaGen's founder, Dr J Ramachandran, talks about his
breakthrough product, his passionate search to find a 'superbug'
killer, and the help he needs from the global society, to complete his
dream of a 'harmful bacteria-free' world.
What are the current areas of research
GangaGen has developed a highly proprietary product called StaphTAME
(also known as P 128) for the control of the superbug Methicillin
Resistant Staphylococcus Aureus (MRSA), which is currently the most
serious hospital-acquired infection. All preclinical development of
StaphTAME has been completed, and a successful pre-IND meeting with the
US Food and Drug Administration (FDA) has been concluded. GangaGen is
preparing to conduct clinical trials of StaphTAME later this year, both
in the US and in India. StaphTAME is a recombinant protein that kills
MRSA and all Staph bacteria very rapidly (in minutes) by a novel
Pseudomonas aeruginosa is the most antibiotic-resistant pathogen after
MRSA, and is the source of major infection in burns and wounds.
GangaGen is developing a proprietary product for the control of
Pseudomonas aeruginosa, that is currently undergoing preclinical
development. GangaGen hopes to advance this product into clinical
trials next year.
GangaGen's research team is also engaged in the discovery and
development of phage-based products for the control of other pathogens
including Clostridium difficile, which often emerge as a secondary
infection following antibiotic treatment, and is rivaling MRSA as a
hospital-acquired infection in the UK.
Is there enough
happening in the area of phage therapy globally? Which are the other
companies working in this area?
GangaGen is a pioneer in developing innovative products based on
phages. Many of the phage companies around the world did not pursue
innovation, but rather focused on the production of natural phages that
have some limitations. Release of endotoxins from the pathogens killed
by phages, immune response to the phage, and potential for acquiring
toxic genes from a pathogen and transferring it to the beneficial
bacteria present in the patient, are some of the problems in the use of
naturally occurring whole phages.
GangaGen developed the proprietary 'Lysis-deficient Phages' to
circumvent these problems through genetic engineering of the natural
phages. Lysis-deficient phages kill the pathogens as effectively as the
natural phages, but due to the deletion of the 'endolysin' gene, do not
release phage or endotoxins, and do not have the opportunity to
transfer toxic genes. Two patents on the Lysis-deficient phages were
issued to GangaGen by the US Patent Office in 2005. This accomplishment
of GangaGen was described in an article in BioSpectrum in July 2004.
Phage Therapeutics in Seattle, Washington, US, was started in 1997 to
develop natural phage against MRSA but closed down in 2003. Exponential
Therapies, the oldest phage company, started in 1994, but closed the
phage program in 2005. There are several small companies developing
natural phage for agricultural use and animal health in various stages
In spite of its
vast potential, why
has the phage technology/therapy failed to win the right recognition in
India, and also in other countries?
It is really unfortunate that phage therapy has not reached its
potential in spite of the remarkable success it demonstrated in the
first half of the last century, both in Europe and India.
Felix d'Herelle, the French-Canadian scientist who demonstrated the
efficacy of phage for the control of shigella infection in the World
War I years in France, came to India in 1927, and showed that cholera
could be effectively controlled with phage. Impressed by this, Morison,
the director of King Edward VII Pasteur Institute in Assam, tried phage
therapy in villages in Assam that had cholera epidemics every year.
Nowgong, the village that used phage treatment had less than 10 deaths
due to cholera, whereas Habibganj that did not use phage had over 300
deaths. This study was published in the Transactions of the Royal
Society for Tropical Medicine and Hygiene in London in 1935, and is
described on the GangaGen website.
The reason that phage therapy did not emerge as the treatment of choice
for infection are manifold. In order to use phage as a therapy, the
pathogen causing the infection must be properly diagnosed, so that the
appropriate phage can be used. Phages are highly specific, and a given
phage such as the cholera phage, will kill only cholera bacteria and
not others. Diagnosis is not easy even now, and in the early part of
the past century, it was extremely difficult. When Penicillin was
discovered in the late 1920s, physicians in the Western world abandoned
phage and embraced antibiotics, since they had broad-spectrum activity.
Penicillin could be used to treat many infections. In fact, it is the
overuse and misuse of antibiotics over the last six decades, that led
to the emergence of robust antibiotic-resistant pathogens like MRSA.
The second major reason why pharmaceutical companies did not pursue
phage therapy is the perceived lack of patent protection for naturally
In the context of debate on the presence of superbugs and predictions
of the end of antibiotics, what role can phage therapy play to restrict
Lysis-deficient phage and phage-based products like StaphTAME can play
a very important role in controlling the superbugs, as they have been
shown to effectively kill these antibiotic-resistant pathogens in the
laboratory as well as in animal models. What stands in the way of phage
products is the lack of proper placebo-controlled double blind clinical
trials according to the US FDA standards. GangaGen is preparing to
rectify this by conducting the phase I/II/III trials with StaphTAME.
What are the
achieved by phage therapy in recent years?
Apart from the results achieved by GangaGen, a company in the UK has
reported that middle ear infection could be treated successfully with
phage against Pseudomonas bacteria.
What hurdles do you
anticipate in the
path of phage therapy solutions?
The main hurdle is the lack of adequate financing to complete the
clinical trials quickly.
Narayanan Suresh and Jahanara Parveen