Seventy percent of all infections in the United States arenow drug resistant, turning the speedy increase of drug-resistant bacteria intoa very critical medical issue. However, in spite of the seriousness of thisburgeoning disaster, a significant number of pharmaceutical giants haveforsaken the creation of anti-infectives in favor of more financially promisingtreatments. As a result, the number of novel anti-infectives passing throughclinical trials remains tiny.
There is strong demand for new anti-infectives, but majorfactors are slowing down their commercialization. There are, however, a varietyof promising initiatives, including advances involving non-antibioticanti-infectives and host defense proteins.
Urgent need for freshtreatments
According to the Centers for Disease Control and Prevention(CDC), in the United States alone, almost two million patients contract aninfection in the hospital annually, and almost 100,000 of them die each year asa result of drug-resistant infections—making this the sixth leading cause ofdeath in the country. This number is up from 13,000 such patient deaths in1992.
And the crisis is worldwide. In a 2009 survey, 50 percent of14,114 patients in 1,265 intensive-care units in 75 nations were infected, andthese infected patients faced double the chance of death in the hospitalcompared to patients who had not contracted infections.
Possibly most unnerving is the damage being wrought byso-called "superbugs" such as Methicillin-resistant Staphylococcus aureus (MRSA) and the New DelhiMetallo-beta-lactamase 1 (NDM-1). S.aureus is a type of bacteria that colonizes the skin and nostrils of asmuch 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 resistanceagainst any beta-lactam antibiotic (a group including penicillins, carbapenems,monobactams and cephalosporins) in addition to macrolides, streptogramins andlincosamides. On top of this, MRSA exhibits emerging resistance totetracycline, quinolones and sulfa drugs. MRSA is currently responsible for 19,000 fatalities, 369,000 hospitalizationsand seven million doctor/emergency room visits every year. It results inextended lengths of stay in hospitals and billions of dollars in extrahealthcare expenses.
Meanwhile, NDM-1 is an enzyme that makes bacteria resistantto a wide range of beta-lactam antibiotics. These include the antibiotics ofthe carbapenem family, which are a mainstay for the treatment ofantibiotic-resistant bacterial infections. The gene for NDM-1 is one member ofa large family of genes that encodes beta-lactamase enzymes known ascarbapenemases. NDM-1 was originally found in a Klebsiella pneumoniae isolate from a Swedish patient of Indianorigin in 2008. It was subsequently found in bacteria in India, Pakistan, theUnited Kingdom, the United States, Canada, Japan and Brazil. The most commonbacteria that make this enzyme are Gram-negative bacteria such as Escherichia coli and K. pneumoniae. However, the gene forNDM-1 can travel from one strain of bacteria to another via horizontal genetransfer.
What factors are to blame for hindering thecommercialization of novel anti-infectives? A novel agent more powerful thanany of those now on the market would probably be held in reserve for only themost stubborn infections, lowering its commercial potential; and virtually allanti-infectives are being constrained in use—particularly in agriculture—forthe purpose of slowing the creation of more drug-resistant types of infectiouspathogens. On top of this is the problem that anti-infectives usually are givenas an acute-care regimen for a week or a few months, rather than to treat achronic condition, and the commercial potential of any anti-infective starts tolook bleak.
Additionally complicating the situation is the followingproblem, which is exclusive to the anti-infectives sector: Antibiotics andother antimicrobials are the sole drugs that lose their efficacy withtime—especially with widespread or inappropriate use—and therefore must bereplaced. These factors exacerbate the research and development burden forcommitted drug developers and drastically limit the long-term market potentialof any particular anti-infective agent.
Innovativeinitiatives
In light of these obstacles, in addition to the technicalcomplexity of creating novel antibiotics and the imposing timescales involved,a number of companies are assessing alternative approaches. A variety ofrationales lie behind the search for variant strategies.
For example, it is increasingly being recognized thatcreating new antibiotics in existing classes of compounds that are exhibitingdrug resistance may not help. This is due to the fact that bugs have evolved aresistance to a member of a particular class of drug—e.g., the fluoroquinoloneclass of antibiotics, such as Cipro—and can apply the same resistance mechanismto the remainder of the class. And as we have noted earlier for NDM-1,resistance mechanisms can also be transferred to other bacteria, making theresistance problem a larger issue.
Also, it is possible that relatively younger and smallercompanies, although with just as much of an eye on the bottom line as theirlarger counterparts in the pharmaceutical arena, are perhaps more flexible whenit comes to conceptual approaches and less invested in conservative paths tofulfilling the need for novel treatments. Companies that were created after thecrisis came to a head may have a different attitude toward solving it.
So what type of work is now being done to clear the logjamin the creation of novel solutions? One path involves the creation ofanti-infective compounds for the treatment and prevention ofantibiotic-resistant infections. Researchers have synthesized novel, syntheticN-chlorinated antimicrobial molecules specifically designed and developed tomimic the body's natural defense against infection. These compounds appear tomaintain biological activities while exhibiting improved stability over thenaturally 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 virusesand fungi. It is conceivable that these types of compounds have the power todeliver the same or improved efficacy as antibiotics, and can address theincreasingly important issue of antibiotic resistance by using a novelmechanism of action.
This type of compound may also find utility in the battleagainst impetigo, a highly contagious superficial bacterial infection of theskin that mostly affects children. The majority of cases are triggered by Staphylococcus aureus, Streptococcus pyogenes or a combinationof both organisms. However, MRSA is being seen with greater frequency in thispopulation. Impetigo is currently being treated with antibiotic ointments towhich bacteria may evolve resistance. A recent proof-of-concept study offeredcompelling evidence of the activity of an anti-infective compound topical gelin the treatment of impetigo in children.
It should be noted as well that the same class of compoundshave 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 themajority of hospital infections and increasingly evade the effects ofantibiotics.
An independent approach involves innovation in thelaboratory, involving the search for a novel class of antibiotic compounds thatattack bacteria in new ways, specifically via mechanisms that bacteria have notyet recognized. Some scientists are now turning to biomimetics, the study ofsuccessful strategies adopted by plants and animals, for inspiration in thesearch for novel antibiotics. In 1986, it was discovered that frog skin harborsarmies of protein-like germ fighters that attack and destroy bacteria thatthreaten infection. This finding was the first of the class of agents known ashost defense proteins, which have subsequently been discovered in almost allhigher life forms, including humans. Host defense proteins are an important componentof the immune system—a first line of defense against bacteria. Since studiesshow that bacteria have little or no ability to resist antimicrobial peptides,one of the most interesting possibilities inspired by this discovery is thedevelopment of novel forms of antibiotics to battle bacteria that have evolvedresistance to conventional drugs.
It is currently known that it is possible to develop smallmolecules that are able to mimic the key biological traits of natural hostdefense proteins. Specifically, a compound can be based on this model thatpunches holes directly in bacterial cell membranes, resulting in thedestruction of the genetic machinery frequently responsible for bacterialresistance and minimizing the probability that such resistance will develop.
As we have noted earlier, the need for novel solutions tothe issue of antibiotic-resistant bacteria is a serious one. Given the factthat 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-antibioticanti-infectives drugs as well as the development of drugs mimicking hostdefense proteins. Should these efforts come to fruition, in the form ofcommercially available treatments in hospitals, it could herald a healthier andsafer era for all of us.
Dr. Ron Najafi ischairman and CEO of NovaBay Pharmaceuticals Inc., an Emeryville, Calif.-basedbiotechnology company developing anti-infective compounds for the treatment andprevention of antibiotic-resistant infections. He can be reached atron@novabaypharma.com.
