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Guest Commentary: Developing new treatments for antibiotic-resistant bacteria
Seventy percent of all infections in the United States are now drug resistant, turning the speedy increase of drug-resistant bacteria into a very critical medical issue. However, in spite of the seriousness of this burgeoning disaster, a significant number of pharmaceutical giants have forsaken the creation of anti-infectives in favor of more financially promising treatments. As a result, the number of novel anti-infectives passing through clinical trials remains tiny.
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.
Urgent need for fresh treatments
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.
Possibly most unnerving is the damage being wrought by so-called "superbugs" such as Methicillin-resistant Staphylococcus aureus (MRSA) and the New Delhi Metallo-beta-lactamase 1 (NDM-1). S. aureus is a type of bacteria that colonizes the skin and nostrils of as much as 30 percent of the U.S. population. A frequent cause of mild infections, it can become virulent when it enters the body. MRSA exhibits resistance against any beta-lactam antibiotic (a group including penicillins, carbapenems, monobactams and cephalosporins) in addition to macrolides, streptogramins and lincosamides. On top of this, MRSA exhibits emerging resistance to tetracycline, quinolones and sulfa drugs. MRSA is currently responsible for 19,000 fatalities, 369,000 hospitalizations and seven million doctor/emergency room visits every year. It results in extended lengths of stay in hospitals and billions of dollars in extra healthcare expenses.
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.
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.
It should be noted as well that the same class of compounds have exhibited efficacy against NDM-1, as well as the six so-called "ESKAPE" pathogens—Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species—that cause the majority of hospital infections and increasingly evade the effects of antibiotics.
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.
It is currently known that it is possible to develop small molecules that are able to mimic the key biological traits of natural host defense proteins. Specifically, a compound can be based on this model that punches holes directly in bacterial cell membranes, resulting in the destruction of the genetic machinery frequently responsible for bacterial resistance and minimizing the probability that such resistance will develop.
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 firstname.lastname@example.org.