Superbug Nemesis: NTU VirusBom


2011 / 5月

Lin Hsin-ching /photos courtesy of Jimmy Lin /tr. by Jonathan Barnard

Readers of detective novels are familiar with "indiscriminate killers"-murderers who aren't picky about their victims. Once such a killer's victims start to be found at a favored kind of location, the bodies will pile up until the perpetrator is caught.

Although the term "indiscriminate killer" has a horrifying ring to it, medical researchers studying viruses and mutating bacteria have long yearned for an indiscriminate killer of their own-a biocide that would destroy all manner of vexing viruses and bacteria. Such a substance would greatly simplify disease prevention work and help avert epidemics of contagious diseases and unnecessary loss of human life.

However such a cure-all might sound like the stuff of fantasy, something approaching an indiscriminate killer of contagious pathogens is in fact already here. Witness the NTU VirusBom, an organic compound developed by the National Taiwan University Nano-BioMems Group in 2009. Described as the "king of kings" among sterilizers, the compound wipes out a remarkable array of viruses and germs. It has already been shown to be effective in destroying various flu viruses, enteroviruses and golden staph. It even vanquishes NDM-1 superbugs, against which antibiotics are powerless.

The compound has the potential to play a huge role in disease prevention. But exactly what mechanism does it employ to attack viruses and kill germs? And what sorts of new applications might it lend itself to?

Every year, during the fall and winter flu season or the spring and summer enterovirus season, parents make anxious posts on social networking sites, exchanging information about various products touted as preventing the spread of disease, such as ethyl alcohol, surgical masks, hand sanitizers, and chlorine dioxide. Over the last two years, the NTU VirusBom spray has been rapidly rising in popularity. It's the first product known to work against enterovirus 71 and the H1N1 flu virus, among other viral and bacterial pathogens.

VirusBom's chemical mechanism

The NTU VirusBom is an enzyme mimic with oxidation-reduction potential. Upon contact with viruses and bacteria, the VirusBom destroys them by rupturing their covalent bonds. But in actuality the NTU VirusBom isn't the first compound aimed at combating viruses and germs to employ that mechanism. It was predated by the NTU Anti-SARS No. 1 compound.

Lin Shiming, a professor at the Center for Optoelectronic Biomedicine at NTU's College of Medicine, was the lead re-searcher of the team that developed the compound. He recalls that it was in fact discovered quite accidentally while he was in the pursuit of another goal. In March of 2003, Taiwan's first confirmed SARS patient, a businessman with the surname Qin, was admitted to National Taiwan University Hospital. First, Kao Chuan-liang, the director of clinical virology in the Department of Laboratory Medicine at NTUH, successfully took an isolate of the virus from the patient, and then Lin, whose research focus is on nanomedicine and medical metrology, was asked by Chen Ding-shinn, then dean of NTU's College of Medicine, and Yang Pan-chyr, then chair of the Department of Internal Medicine, to undertake the onerous task of mapping SARS' molecular structure at the nanoscale.

Anchor molecules save the day

Since SARS is so highly contagious, Lin didn't want to put an assistant in harm's way and decided to bear all the risk himself. He sent his wife and children to his family in Nantou and stayed day and night in his laboratory, which was assessed with a "level-two biohazard" rating. There he devoted himself to precisely mapping the three-dimensional nanostructure of the virus with an atomic microscope.

Like all coronaviruses, SARS has a crown-like shape, which is made up of "spike proteins" with directional properties. To measure them accurately it is necessary to use artificial organic compounds ("anchor molecules") to "bind" the spike proteins, so that the virus will "stand erect." Only thus is it possible to comprehensively measure the spike proteins' irregular shapes. Relying on his expert knowledge of the chemistry and structure of proteins, Lin Shi-ming selected about a dozen possible anchor compounds and then tested their effects. Much to the team's surprise, when one of them came into contact with the tenacious SARS virus, it caused the complete collapse of its molecular structure. That compound would become the main component of NTU Anti-SARS No. 1.

Among those who contracted SARS, the mortality rate was 11%, so news that the compound could destroy SARS' molecular "crown" caused quite a stir at the time. The research results made the cover of Cellular Microbiology, a prestigious international journal. Yet as the SARS epidemic died down, so too did discussion of Anti-SARS No. 1. It wouldn't be until there was a major outbreak of H1N1 in the spring of 2009 that the compound would once again attract attention.

The secrets of viral collapse

Lin recalls that a reporter from Reuters tracked him down to ask whether the compound might be effective against H1N1. He thought long and hard but couldn't provide a definitive answer. The compound had only been tested on SARS before the rights to it were transferred to a pharmaceutical company, so there was a lack of laboratory data about its effect on other viruses. "Yet the question made me consider the possibility that a new compound could be discovered to combat H1N1."

Drawing on his earlier experience in the lab, Lin developed a new compound to work against the H1N1 virus without much difficulty. By the middle of June 2009, his research team had successfully selected three molecular enzymes that were able to collapse the H1N1 virus. The most effective of the three would later end up being produced for the NTU VirusBom.

"The H1N1 virus is less dangerous than the SARS virus, and consequently students were eager to research it. But preferring to be safe rather than sorry, we all put in applications for a dose of Tami-flu," says a smiling Lin.

In truth, the chemical structures of the two sterilizers are quite different. Anti-SARS No. 1 is an organic compound with only a two-dimensional chemical chain, whereas NTU VirusBom is a synthesized molecular enzyme that has components similar to the proteins that catalyze chemical reactions in the active centers of enzymes. The VirusBom features a much more complex three-dimensional structure that supports oxidation and reduction reactions with other materials. In comparison to Anti-SARS No. 1, which is solely an oxidizer, it is much easier for the NTU VirusBom to break the covalent bonds between a virus's glycoproteins and lipoproteins. Consequently, it has a much wider range of uses.

Follow-up research also proved that in addition to effectively combating the H1N1 virus and the H2N2 and H3N2 seasonal flu viruses, the compound also attacks H5N2 avian flu, enterovirus 71, and the human papillomavirus (which can lead to cervical cancer).

In July of 2009, a pharmaceutical manufacturer gave NTU more than NT$10 million for the rights to the compound, establishing a record for technological transfer at NTU. Within two months sprays and soaps featuring the compound hit the market.

Sterilizing the hospital

The effectiveness of the NTU VirusBom against various kinds of viruses has been confirmed repeat-edly. Now the academic world has turned to consider whether the compound could be used against highly infectious bacterial "superbugs," which pose even graver medical threats. Target No. 1 was NDM-1, an enzyme that makes bacteria resistant to nearly all antibiotics.

NDM-1 is resistant to many drugs and can replicate itself outside the chromosomes of many germs. By transmitting itself with Escherichia coli, Klebsiella pneumonia and other pathogens, it often proves deadly. First discovered at a hospital in New Delhi, it gradually spread, and outbreaks have been recorded in Pakistan, Hong Kong and even Japan.

The most frightening aspect of NDM-1 is that it renders almost all antibiotics ineffective. Currently, only a few last-line-of-defense antibiotics, such as tigecycline (Tygacil) and polymyxin E (Colistin), have been shown to have any effect on NDM-1-bearing bacteria in clinical trials. Patients are largely left to rely on their own immune systems to battle them.

In mid-September of 2010, a crew from the TVBS show Super Taste was mysteriously fired upon while on location in India. Two cameramen were seriously injured. One of them came down with NDM-1 while being treated in India. His return to Taiwan caused alarm in some quarters. Fortunately, he was symptomless and avoided a troublesome fever, pneumonia, or septicemia. After a short period in isolation, he recovered completely. His return didn't prompt an epidemic in Taiwan.

Yet the bacterial cultures taken from his body attracted a lot of attention in academia. Lai Hsin-chih, director of the Graduate Institute of Medical Biotechnology at Chang Gung University, had long been interested in controlling the spread of drug-resistant germs inside hospitals. With access to those cultures, he applied for a grant to research superbugs from the ROC Centers for Disease Control.

Lai points out that the warm and damp hospital environment is the site of frequent applications of disinfectants. Although the disinfectants kill most germs, a small number will prove resistant. NDM-1 isn't entirely unique. Other enzymes similarly confer resistance to many antibiotics on superbug strains of bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus.

These bacteria, widely present in hospitals, typically affect only those with compromised immune systems, such as terminal cancer patients, or those who have had major surgery, including organ transplants. The healthy usually are symptomless when they contract them. But these superbugs add a huge potential threat of post-operative complications for those who are ill.

Indiscriminate biocide

In order to ascertain whether the NTU VirusBom would also be effective against superbugs, Lai asked for assistance from the research team at NTU, which provided different concentrations of the compound. The results showed that NDM-1-bearing bacteria, Acinetobacter baumannii, Pseudomonas aeruginosa, and the like were all wiped out within a minute of coming into contact with the NTU VirusBom at a concentration of 300 parts per million or higher.

Lai explains that, similar to how it breaks apart viruses, the NTU VirusBom employs special chemical structures to attack bacteria. They integrate themselves into the cell membranes of the bacteria, and then the unstable functional groups they carry interact with organic components of the bacterial cell, such as carbohydrates, proteins and lipids. Fi-nally, the cells, having lost their membranes and nutrients, simply die.

What's more, the NTU VirusBom employs a biophysical mechanism to destroy bacteria. This mode of action is different from that of antibiotics, which attack specific biochemical targets, and is much more difficult for bacteria to build resistance against.

Nevertheless, Lai also believes that the NTU VirusBom-that indiscriminate killer of viruses and bacteria-has disadvantages too. Its strong point is that it is an extremely good killer of germs outside the body-for instance when sprayed on surfaces in hospitals that can commonly harbor and transfer germs, such as doorknobs, elevator buttons, tabletops, and areas near and under sickbeds. In such places it can reduce the potential for spreading pathogens. But because the NTU VirusBom is an "indiscriminate killer," it also kills off beneficial bacteria, so it's hard to imagine how it could be used internally like antibiotics or other antimicrobial drugs.

Preventing disease

Apart from its effectiveness against viruses and bacteria, the compound has also shown to be effective in fighting athlete's foot fungus and Candida albicans, a common cause of vaginal yeast infections.

Yet some people wonder if this molecular enzyme, which demonstrates such miraculous effects in destroying pathogens, would similarly destroy skin cells if sprayed directly on them.

Lin Shiming, who has carried out numerous in-vitro and animal studies, explains that most viruses have diameters of 30-100 nanometers, whereas bacterial germ cells and fungal cells range in diameter from 0.5-3 microns and 3-10 microns respectively. Human and animal cells, on the other hand, measure 40-50 microns. Consequently, they pose difficult targets for NTU VirusBom to attack. What's more, human and animal cells are eukaryotes, which have substantial structural differ-ences from prokaryotes such as viruses and bacteria. Consequently, NTU VirusBom does absolutely no damage to animal cells.

Currently, NTU VirusBom is being marketed as "general merchandise" ra-ther than as a "medical product." Scientists recommend that it be sprayed on doorknobs, keyboards, telephones, elevator buttons and other commonly used objects at hospitals, daycare facilities and schools. What's more, during epidemics, it can be used as a disinfectant and applied directly to the hands, like alcohol wipes.

"Whether it can be applied topically to fight athlete's foot or yeast infections," Lin says, "will require more follow-up research and clinical tests."

In the current era of high population density and frequent contact between people from different regions of the globe, the speed at which viruses and germs can mutate and be transmitted often catches people unprepared. In light of the various kinds of unpredictable contagious diseases that people will be inevitably dealing with in the future, we've got to start developing more weapons in our disease-prevention arsenal. The NTU VirusBom is a fine example of successful R&D by Taiwan's academic community.



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