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 Guest Commentary: Developing new treatments for antibiotic-resistant bacteria
July 2011
SHARING OPTIONS:
There is strong demand for new anti-infectives, but major
factors are slowing down their commercialization. There are, however, a variety
of promising initiatives, including advances involving non-antibiotic
anti-infectives and host defense proteins.
According to the Centers for Disease Control and Prevention
(CDC), in the United States alone, almost two million patients contract an
infection in the hospital annually, and almost 100,000 of them die each year as
a result of drug-resistant infections—making this the sixth leading cause of
death in the country. This number is up from 13,000 such patient deaths in
1992.
And the crisis is worldwide. In a 2009 survey, 50 percent of
14,114 patients in 1,265 intensive-care units in 75 nations were infected, and
these infected patients faced double the chance of death in the hospital
compared to patients who had not contracted infections.
Meanwhile, NDM-1 is an enzyme that makes bacteria resistant
to a wide range of beta-lactam antibiotics. These include the antibiotics of
the carbapenem family, which are a mainstay for the treatment of
antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of
a large family of genes that encodes beta-lactamase enzymes known as
carbapenemases. NDM-1 was originally found in a Klebsiella pneumoniae isolate from a Swedish patient of Indian
origin in 2008. It was subsequently found in bacteria in India, Pakistan, the
United Kingdom, the United States, Canada, Japan and Brazil. The most common
bacteria that make this enzyme are Gram-negative bacteria such as Escherichia coli and K. pneumoniae. However, the gene for
NDM-1 can travel from one strain of bacteria to another via horizontal gene
transfer.
What factors are to blame for hindering the
commercialization of novel anti-infectives? A novel agent more powerful than
any of those now on the market would probably be held in reserve for only the
most stubborn infections, lowering its commercial potential; and virtually all
anti-infectives are being constrained in use—particularly in agriculture—for
the purpose of slowing the creation of more drug-resistant types of infectious
pathogens. On top of this is the problem that anti-infectives usually are given
as an acute-care regimen for a week or a few months, rather than to treat a
chronic condition, and the commercial potential of any anti-infective starts to
look bleak.
Additionally complicating the situation is the following
problem, which is exclusive to the anti-infectives sector: Antibiotics and
other antimicrobials are the sole drugs that lose their efficacy with
time—especially with widespread or inappropriate use—and therefore must be
replaced. These factors exacerbate the research and development burden for
committed drug developers and drastically limit the long-term market potential
of any particular anti-infective agent.
Innovative
initiatives
In light of these obstacles, in addition to the technical
complexity of creating novel antibiotics and the imposing timescales involved,
a number of companies are assessing alternative approaches. A variety of
rationales lie behind the search for variant strategies.
For example, it is increasingly being recognized that
creating new antibiotics in existing classes of compounds that are exhibiting
drug resistance may not help. This is due to the fact that bugs have evolved a
resistance to a member of a particular class of drug—e.g., the fluoroquinolone
class of antibiotics, such as Cipro—and can apply the same resistance mechanism
to the remainder of the class. And as we have noted earlier for NDM-1,
resistance mechanisms can also be transferred to other bacteria, making the
resistance problem a larger issue.
Also, it is possible that relatively younger and smaller
companies, although with just as much of an eye on the bottom line as their
larger counterparts in the pharmaceutical arena, are perhaps more flexible when
it comes to conceptual approaches and less invested in conservative paths to
fulfilling the need for novel treatments. Companies that were created after the
crisis came to a head may have a different attitude toward solving it.
So what type of work is now being done to clear the logjam
in the creation of novel solutions? One path involves the creation of
anti-infective compounds for the treatment and prevention of
antibiotic-resistant infections. Researchers have synthesized novel, synthetic
N-chlorinated antimicrobial molecules specifically designed and developed to
mimic the body’s natural defense against infection. These compounds appear to
maintain biological activities while exhibiting improved stability over the
naturally occurring N-chlorinated antimicrobial molecules. In a clinical study,
such compounds have been shown to be highly effective against bacteria,
including some multi-drug resistant strains such as MRSA, as well as viruses
and fungi. It is conceivable that these types of compounds have the power to
deliver the same or improved efficacy as antibiotics, and can address the
increasingly important issue of antibiotic resistance by using a novel
mechanism of action.
This type of compound may also find utility in the battle
against impetigo, a highly contagious superficial bacterial infection of the
skin that mostly affects children. The majority of cases are triggered by Staphylococcus aureus, Streptococcus pyogenes or a combination
of both organisms. However, MRSA is being seen with greater frequency in this
population. Impetigo is currently being treated with antibiotic ointments to
which bacteria may evolve resistance. A recent proof-of-concept study offered
compelling evidence of the activity of an anti-infective compound topical gel
in the treatment of impetigo in children.
An independent approach involves innovation in the
laboratory, involving the search for a novel class of antibiotic compounds that
attack bacteria in new ways, specifically via mechanisms that bacteria have not
yet recognized. Some scientists are now turning to biomimetics, the study of
successful strategies adopted by plants and animals, for inspiration in the
search for novel antibiotics. In 1986, it was discovered that frog skin harbors
armies of protein-like germ fighters that attack and destroy bacteria that
threaten infection. This finding was the first of the class of agents known as
host defense proteins, which have subsequently been discovered in almost all
higher life forms, including humans. Host defense proteins are an important component
of the immune system—a first line of defense against bacteria. Since studies
show that bacteria have little or no ability to resist antimicrobial peptides,
one of the most interesting possibilities inspired by this discovery is the
development of novel forms of antibiotics to battle bacteria that have evolved
resistance to conventional drugs.
As we have noted earlier, the need for novel solutions to
the issue of antibiotic-resistant bacteria is a serious one. Given the fact
that the creation of traditional anti-infectives has lessened in recent years,
the most promising avenues for future progress may come from so-called
“non-traditional” routes, such as the development of non-antibiotic
anti-infectives drugs as well as the development of drugs mimicking host
defense proteins. Should these efforts come to fruition, in the form of
commercially available treatments in hospitals, it could herald a healthier and
safer era for all of us.
Dr. Ron Najafi is
chairman and CEO of NovaBay Pharmaceuticals Inc., an Emeryville, Calif.-based
biotechnology company developing anti-infective compounds for the treatment and
prevention of antibiotic-resistant infections. He can be reached at
ron@novabaypharma.com.
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