How the Flintstones can Help the Jetsons: History Lessons for Modern Medicine

By Lori Bystrom, PhD

Many of us look forward to a future of convenience with magical gadgets and miracle cures, perhaps something akin to the lifestyle of the cartoon characters on The Jetsons. The show’s optimistic portrayal of the future depicts our fascination with modern technology – an interest that stems not only from our desire for new and improved modes of transportation and communication, but also from our desire for new and better medicine.

 

The future of medicine may seem promising, but understanding the past may be vital for making medical dreams come true. Just as the stone-age characters from The Flinstones are capable of helping the futuristic characters of The Jetsons fix their time machine (see The Jetsons Meet The Flinstones clip from 1:00 to 1:17), so too can our long-departed ancestors help us in ways that will benefit us in the future (perhaps in less barbaric ways than hitting something with a club). In other words, medical advancements, although conventionally based on research using modern technology, can also be derived from medical information of the ancient past.

 

Nowhere is this better exemplified than in the recent discovery of a plant-based eye infection remedy found in a 1,000 year old medical text. This finding was recently presented at the British Society for General Microbiology Annual Conference by researchers at the University of Nottingham in England and Texas Tech University in the United States. They found that the 9th century Anglo-Saxon book, known as Bald’s Leechbook, contained a remedy for an eye infection that consisted of a mixture of garlic, onion or leeks, wine, and bile (from cow’s stomach) that was boiled and fermented in a brass vessel. Amazingly, the recreation of this ancient remedy proved to be effective against the resilient methicillin-resistant Staphylococcus aureus (MRSA), both in vitro and on wounds. In fact, it was found to be more effective than one of the antibiotics (vancomycin) currently used to treat the modern day superbug (see this article). Although clinical trials need to be conducted to confirm the beneficial effects of this medicinal preparation, this is an extraordinary start for a potential drug.

 

Should we be surprised that some of these ancient remedies actually have therapeutic value? Back in the day, when clinical trials did not exist and ethical practices were not necessarily enforced, there was probably a great deal of trial and error as people tried medicines on each other. The only medicines that were recorded were probably those that worked, while ineffective treatments may or may not have been noted. Interestingly, some of the traditional medicines may have been inspired by how animals treated their ailments (an area of study known as zoopharmacognosy). There also may have been minimal repercussions for failed treatments (no lawsuits?), and therefore maybe more freedom for finding medical cures. Moreover, if a treatment was found to be effective nobody probably had to wait for approval from any organization such as the Food and Drug Administration (FDA).

 

Regardless of what happened in the past, it is apparent there are valuable lessons we can learn from our ancestors. For instance, the ancient practice of fecal transplantation is now gaining acceptance in modern medicine. As far back as the 4th century, Ge Hong, a traditional Chinese medicine doctor, used fecal material to treat his patients with food poisoning or severe diarrhea. Just recently, the FDA approved the use of fecal transplants for specific gastrointestinal problems. The use of leeches for the treatment of venous congestion, among other ailments, is another example of modern medicine embracing old technology (see this article). There are numerous conventional medications that also have roots in the distant past (e.g. aspirin). Any book on the history of medicine will provide more information on this subject matter.

 

All of these examples suggest that medical research is limited if it turns a blind eye to the past. Moreover, the medical community needs to address the polar opposite views on traditional/natural medicines: those that think all natural products/traditional remedies are safe and those that think all traditional medicines/natural therapies are inherently bad. What it really comes down to is what is effective and not what resonates better to different patients or doctors. More scientific research needs to assess whether these treatments are safe and effective, while identifying those that may be snake oil. The journalist and information designer, David McCandless, beautifully illustrates some of these differences on his website.

 

Modern medicine should keep an open mind while researchers continue to investigate ancient remedies and screen out the good from the bad. It is appropriate that a small division of the National Institute of Health, known formerly as the National Center for Complementary and Alternative Medicine, was renamed as the National Center for Complementary and Integrative Health. Unconventional or traditional medicines that are effective are not the ‘alternative’, but perhaps the best option or one that can be integrated with other medical treatments.

 

As we move forward in medicine, we might want to keep digging up the past so we are prepared to combat new diseases and improve current treatments. The future of medicine may just need, as George Jetson puts it nicely, “a little stone-age technology.”

The Hunt for the Holy Grail: A Potential Vaccine against MRSA

 

By Elizabeth Ohneck, PhD

Vaccines represent the “holy grail” in prevention and treatment of infectious diseases. Effective vaccines have allowed the eradication of small pox and contributed to drastic declines in cases of diseases such as polio, measles, and pertussis (whooping cough). As bacterial pathogens become more resistant to a broader spectrum of antibiotics, the desire to develop vaccines against these offenders to prevent disease altogether heightens.

 

Staphylococcus aureus is a common cause of skin and skin structure infections (SSSIs), as well as post-surgical and wound infections. SSSIs, which frequently present as abscesses in the upper layers of skin tissue, can serve as sources of more serious infections with high mortality rates, such as pneumonia, endocarditis, and bloodstream infections, when the bacteria break through the upper layer of tissue and invade other sites of the body. With the high prevalence of methicillin-resistant S. aureus (MRSA) depleting our antibiotic arsenal, S. aureus infections have become difficult to treat, spurring intense investigation into vaccine development.

 

A group from UCLA recently developed a potential vaccine, NDV-3. This vaccine is actually based on a protein from the fungal pathogen Candida albicans, which causes diseases such as thrush and yeast infections. The C. albicans protein is similar in structure to S. aureus adhesins, proteins on the bacterial surface that allow the bacterial cell to stick to host cells. In preliminary studies, the NDV-3 vaccine was shown to be protective against both C. albicans and S. aureus. In a recent paper in PNAS, Yeaman et al. examine in detail the efficacy of this vaccine in MRSA SSSI and invasive infection.

 

To determine the efficacy of the NDV-3 vaccine in prevention of S. aureus SSSIs, the researchers vaccinated mice with NDV-3, and administered a “booster shot” 21 days later. Two weeks after the booster, the mice were infected with S. aureus by subcutaneous injection, or injection just under the skin, to induce abscess formation. Abscess progression and disease outcomes were then monitored for 2 weeks.

 

Abscess formation was slower and the final size and volume of abscesses were smaller in vaccinated mice compared to control mice. In addition, mice vaccinated with NDV-3 were able to clear S. aureus abscesses by 14 days after infection, whereas abscesses in control mice were not resolved. Using a S. aureus strain expressing luciferase, a protein that emits light, the researchers were able to watch proliferation of the bacteria within the abscesses by measuring the strength of the luciferase signal. Vaccination with NDV-3 resulted in a significantly weaker luciferase signal than in unvaccinated mice, indicating NDV-3 vaccination prevents growth of the bacterial population. This finding was supported by a decrease in the number of CFUs (colony-forming units), an estimate of the number of viable bacteria, isolated from abscesses of vaccinated versus unvaccinated mice. Importantly, the researchers conducted these experiments with 3 distinct MRSA strains and observed similar results for each. Together, these findings demonstrate that while the NDV-3 vaccine does not completely prevent SSSIs under these conditions, vaccination can significantly reduce severity.

 

As skin infections can often serve as a source for more serious disseminated infections, the researchers also examined the effect of NDV-3 on the spread of S. aureus from the original site of infection. While control mice developed small abscesses in deeper tissue layers, vaccinated mice showed little to no invasion of infection. Additionally, significantly fewer bacteria were found in the kidneys of vaccinated mice compared to control mice, indicating NDV-3 can prevent the spread of S. aureus from skin infection to more invasive sites.

 

To examine how NDV-3 was stimulating a protective effect against MRSA, the researchers measured the amount of molecules and cells important for immune response to MRSA in vaccinated and unvaccinated mice. Abscesses of vaccinated mice showed a higher density of CD3+ T-cells and neutrophils, as well increased amounts of the cytokines, or immune cell signaling molecules, IL-17A and IL-22. Vaccinated mice also showed higher amounts of antibodies against NDV-3, as well as increased production of antimicrobial peptides, small proteins with antibiotic activity produced by host cells. Thus, the NDV-3 vaccine helps encourage a strong immune response against MRSA.

 

The NDV-3 vaccine was recently tested in a phase I clinical trial and found to be safe and immunogenic (i.e., stimulates an immune response) in healthy human volunteers. While the vaccine in it’s current form doesn’t prevent S. aureus infections altogether, it could help make infections easier to treat by slowing bacterial growth, preventing spread to other tissues, and boosting the host immune defenses. Further research on this vaccine may also lead to a form that is more protective and can better prevent infections.

 

Stopping the Unstoppable: New Drug Candidates Against MRSA

By Elizabeth Ohneck

Rapidly spreading antibiotic resistance is threatening our arsenal of treatment options against bacterial pathogens. One microorganism of particular concern is methicillin-resistant Staphylococcus aureus, or MRSA, which causes diseases ranging from mild skin infections to pneumonia and sepsis. While originally primarily found in immunocompromised patients in hospital settings, MRSA is now being acquired by otherwise healthy individuals in the community. The development of effective new antibiotics requires identification of drug targets essential to bacterial survival, resistant to the development of mutations, and not found in humans. Recently, the MRSA pyruvate kinase (PK) was identified as one such target, as it is an important player multiple metabolic pathways in MRSA. While humans and other mammals also have PK, the MRSA and mammalian PK enzymes significantly differ in structure, allowing specific targeting of MRSA PK. Additionally, because this enzyme is critical in metabolism, it is expected that PK will be less tolerant to the development of mutations, reducing the risk of acquiring resistance to drugs targeting PK.

 

Previous chemical screens identified several indole-based compounds that were able to selectively inhibit MRSA PK and kill a panel of other Gram-positive bacteria. The road from discovery to drug is long, and in a recent paper in Bioorganic and Medicinal Chemistry, Kumar et al. detail their efforts to optimize these compounds for drug development. Using a chemical scaffold based on a compound previously crystallized bound to PK, the researchers created a panel of bis-indole compounds varying slightly in size, shape, charge, or chemical group content, and examined their antibiotic potential. The ideal optimized drug candidates should both inhibit MRSA PK and kill MRSA at low concentrations, and lack both activity against mammalian PK and toxic effects on human cells.

 

Using a photometric assay for purified MRSA PK activity, Kumar et al. were able to identify several potent inhibitors of MRSA PK. Surprisingly, some of the most effective PK inhibitors were ineffective as antibiotics against S. aureus, as determined by minimum inhibitory concentration (MIC) assays. For a few of these compounds, improving solubility lowered the MIC to an acceptable level, likely by improving the ability of these compounds to enter the bacterial cells. For many others, altering the solubility had little to no effect. The research team wondered if the inability of these compounds to kill S. aureus despite their potent PK inhibitory activity was due to removal from the bacterial cell by efflux pumps, molecular machines in the bacterial cell wall that recognize toxic compounds and actively export them from the cell interior. Efflux pumps are major contributors to the multidrug resistance phenotypes of many bacterial pathogens. By administering the efflux pump inhibitor verapamil with the indole compounds, the researchers were able to drastically reduce the MIC of several compounds, demonstrating some of these molecules can be recognized by MRSA efflux pumps, which creates concern for the development of resistance to these particular compounds and places further constraints on the specific bis-indoles that can be pursued as drug candidates.

 

Several compounds from the panel were found to be both effective PK inhibitors and antibiotics, and Kumar et al. demonstrated that the 3 most effective compounds were active against both a laboratory strain of S. aureus and the MRSA strain MW2. Additionally, they determined that the ability of these compounds to kill S. aureus is dependent on PK activity, as these compounds were unable to kill a strain in which PK had been removed. As the ability of S. aureus to survive without PK requires special growth conditions extremely unlikely to be found in a host during infection, the inability of these compounds to kill a PK mutant is not particularly concerning for drug development. Finally, the research team found that even at high concentrations, the indole compounds were both unable to inhibit mammalian PK and not significantly cytotoxic toward HEK 293 cells, a cell line derived from human embryonic kidney cells.

 

In summary, Kumar et al. have identified several indole-based compounds that are able to efficiently inhibit MRSA PK and kill S. aureus without detrimental effects on mammalian PK or human cells. The lead compounds will be further tested for effectiveness in animal infection models. MRSA PK inhibitors may provide a novel drug treatment against this highly multidrug resistant pathogen.

South East Asia and the Mystery of Malaria Resistance

Chris Spencer

We’re more than used to drug resistance arising in bacterial pathogens. Antibiotic resistance is perhaps most well known in MRSA (methicillin-resistant Staphylococcus aureus) – a bacterial strain that had earned, through its resilience, lethality and prevalence in hospitals, the title of “super bug.” Another example is Mycobacterium tuberculosis, strains of which have (terrifyingly enough) evolved resistances to many of the weapons in our antibiotic arsenal. It’s not just bacteria that have been known to evolve such mechanisms, so today I’ll focus on another bullet dodger: malaria (caused by Plasmodium species – Plasmodium falciparum being the most dangerous). Continue reading “South East Asia and the Mystery of Malaria Resistance”