By Ron Najafi, Ph, D,
Seventy percent of all infections in the United States are now drug-resistant, making the rapid rise of drug-resistant bacteria an extremely serious medical problem. And yet, despite the severity of this growing crisis, a considerable number of pharmaceutical giants have abandoned the development of anti-infectives in favor of more lucrative medicines. Consequently, the number of new anti-infectives passing through clinical trials remains at a trickle.
New Antibiotics Reduced To A Trickle
What factors are responsible for blocking the commercialization of new anti-infectives? A new agent more powerful than those currently on the market would likely be held in reserve for only the most intractable infections, limiting its commercial potential. Nearly all anti-infectives are being restricted in use — particularly in agriculture — in order to slow the development of more drug-resistant strains of infectious pathogens. And, anti-infectives typically are administered as an acute care regimen for a week or a few months, rather than to treat a chronic condition.
Further complicating this issue is the fact that antibiotics and other antimicrobials are the only drugs that lose their efficacy over time — particularly with widespread or inappropriate use — and thus must be replaced. These factors increased the R&D burden for drug developers and sharply curtail the long-term market potential of any given anti-infective agent.
Given these hurdles, as well as the technical complexity of developing new antibiotics and the daunting timelines involved, a number of companies are exploring alternative approaches, for various reasons. For example, it is increasingly being realized that developing additional antibiotics in existing classes of compounds that are showing drug resistance may not help. This is because bugs that have developed a resistance to a member of a specific class of drug (e.g. the fluoroquinolone class of antibiotics, like Cipro) can apply the same resistance mechanism to the rest of the class. And, resistance mechanisms also can be transferred to other bacteria, making the resistance issue a larger problem.
Second, it is conceivable that relatively younger and smaller companies are perhaps more flexible when it comes to conceptual approaches and less invested in traditional paths to solving the need for new treatments.
So, what work is currently under way to break the logjam in the development of new solutions? One approach involves the search for a new class of antibiotic compounds that attack bacteria via mechanisms that bacteria have not yet recognized. Some researchers are now turning to biomimetics, the study of successful strategies adopted by plants and animals, for inspiration in the quest for new antibiotics. In 1986, it was found that frog skin harbors armies of protein-like germ fighters that attack and destroy bacteria that threaten infection. This discovery was the first of the class of agents known as host defense proteins, which have since been found in virtually all higher life forms, including humans. Host defense proteins are a key component of the immune system — a first line of defense against bacteria. Since studies indicate that bacteria have little or no ability to resist antimicrobial peptides, one of the most intriguing possibilities inspired by this discovery is the creation of new forms of antibiotics to fight bacteria that have developed resistance to conventional drugs.
It is now known that it is possible to create small molecules that are able to mimic the key biological properties 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 often responsible for bacterial resistance and minimizing the chances that such resistance will arise.
A separate approach involves the development of anti-infective compounds for the treatment and prevention of antibiotic-resistant infections. It is possible that these classes of compounds have the potential to deliver the same or better efficacy than antibiotics and to address the growing problem of antibiotic resistance by employing a novel mechanism of action. This class of compounds may also find use in the fight against impetigo, a highly contagious superficial bacterial infection of the skin that affects mostly children.
Ron Najafi, Ph.D., is chairman and CEO of NovaBay Pharmaceuticals, Inc., an Emeryville, CA-based biotechnology company developing anti-infective compounds for the treatment and prevention of antibiotic-resistant infections. He can be reached at
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