When the medicine doesn’t work any more: Looking for new weapons against diseases
Bacteria and viruses have got smarter, and some diseases seem to be threatening a comeback. With tried and tested defences losing the race against infections, the series Disease Hunters uncovers the novel treatments coming up.
SINGAPORE: Mention cockroaches and many of us may react with disgust and fear.
But Naveed Khan of the American University of Sharjah in the United Arab Emirates thinks the household pest is the source of the next range of bacteria-killing compounds.
He said: “Cockroaches have been here for more than 300 million years. These species have been so successful in adapting and evolving they must have something, some molecules in them to protect them against infectious diseases.”
The professor hit the jackpot when cellular content in the brains of cockroaches proved effective against the superbug, methicillin-resistant Staphylococcus aureus (MRSA). Superbugs are bacteria that cause infections easily and are resistant to a wide variety of antibiotics.
He found that “just less than 5 microgrammes” of cockroach brain mixture killed more than a million MRSA bacteria, a “100-per-cent kill rate”.
WATCH: How cockroaches could stop the next disease outbreak (4:49)
His findings are among the efforts of a global community of scientists and physicians who are fighting a growing health threat: Many disease-causing bacteria have become resistant to antibiotics, and some parasites have become resistant to other drugs.
If new drugs or treatments are not available quickly, these diseases could develop into global health calamities.
Crucially, new weapons are being developed in the anti-microbial infection race, the series Disease Hunters finds out. But are they enough against increasingly resourceful bacteria and viruses?
In his search for solutions, Khan was inspired when he spotted cockroaches scurrying away as he ushered his children into the bathroom to wash their hands.
“We’re telling our children that we have to constantly wash our hands and use anti-bacterial soaps,” he noted. “How come these species are able to resist or protect themselves against infectious diseases?”
His research into what cockroaches have that is protecting them showed that the brain mixture he tested was toxic only to bacteria, not human cells.
He wants to bring these anti-bacterial molecules for animal testing, as new anti-bacterial compounds must be designed to cope with antibiotic-resistant strains.
“We’re heading towards more or less a pre-antibiotic era, where none of the antibiotics will be effective if we don’t come up with novel anti-bacteria,” he said.
One of these anti-bacterial defences could even be viruses like bacteriophages, or phages for short, which can live within and attack bacteria. They are bacteria’s natural nemesis.
And over the past two years, microbiologist Wilfried Moreira and his team from the National University of Singapore’s Yong Loo Lin School of Medicine have built one of the largest bacteriophage banks in Southeast Asia.
While phage research became less important after the advent of antibiotics, the rise of antibiotic-resistant bacteria has led to its comeback.
“Although Europe and the rest of the world were developing antibiotics, in Georgia and then later on the Soviet Union, bacteriophages have been continuously used for the last 100 years,” Moreira said.
At some point, I think every soldier of the Russian army had vials of bacteriophage preparation on them.
Phages also target specific disease-causing bacteria. “When you use antibiotics, it’s equivalent to carpet bombing. You kill all bacteria indiscriminately, including the very good bacteria,’’ he noted.
“Bacteriophages are like a sniper shot — they only infect and cure very specific bacteria, and they leave the good bacteria intact and unaffected.”
When bacteria develop resistance to phages, the phages also evolve to become stronger. “We’re also developing what we call genetic engineering capabilities … to basically make (phages) stronger and more efficacious,” Moreira added.
One disease that genetic engineering has shown promise against is dengue.
Molecular biologist Omar Akbari of the Division of Biological Sciences at the University of California, San Diego, has genetically engineered Aedes aegypti mosquitoes to produce antibodies to dengue, so that they cannot transmit the virus.
He hopes to release the genetically modified mosquitoes into the wild in order to reduce and eventually eradicate dengue transmission.
Until now, the primary ways of preventing the spread of dengue have been through insecticides and the elimination of mosquito breeding grounds.
However, William Petrie, the director of Miami-Dade County Mosquito Control and Habitat Management in the United States, said the Aedes aegypti mosquito is now resistant to “almost all conventional insecticides”.
In Singapore, the newer solutions being tested include breeding male Aedes aegypti mosquitoes infected with Wolbachia bacteria, which interferes with mosquito reproduction.
READ: Anti-dengue Wolbachia mosquito project shows ‘promising results’; to cover all Tampines, Yishun HDB towns from July
When Wolbachia-infected mosquitoes mate with female Aedes aegypti mosquitoes, the eggs will not hatch. As the mosquito population falls, eventually dengue infection rates will drop.
“In areas where we have … high Aedes aegypti mosquito populations, we’ve seen up to a 90 per cent suppression of the mosquito in the community,” cited Project Wolbachia principal investigator Ng Lee Ching from the National Environment Agency.
Separately, research by Lok Shee-Mei from the Duke-NUS Medical School’s emerging infectious diseases programme has discovered a reason dengue is hard to vaccinate against: The virus changes shape under different conditions.
Using a cryo-electron microscope and 3-D modelling, her team was able to capture images of the virus at different temperatures.
“For vaccine development, the vaccine is used to train your body’s immune system to recognise (the virus),” said the professor.
“So you must put (in) all these different structures that it can change into so that your body will be trained to recognise all of them.”
Shape-shifting is not the only complication — dengue also has four serotypes. But the Agency for Science, Technology and Research’s Singapore Immunology Network (SIgN) is in the advanced stages of developing an antibody that is effective against all four serotypes.
The antibody attaches to structures on the virus like a “key entering the lock”, said Laurent Renia, the former executive director of SIgN and current executive director of the Infectious Disease Horizontal Technology Centre.
This, in turn, triggers the immune system to destroy the virus.
Besides dengue, mosquitoes transmit malaria through bites from the female anopheles mosquito.
Although the World Health Organisation declared Singapore to be malaria-free in 1982, the disease is prevalent in many countries, and there are tens of cases in the Republic each year, almost all of which are imported.
So researcher Pablo Bifani, the principal investigator at SIgN, is testing a new drug that could target multiple stages of plasmodium vivax, the most widespread malaria parasite, in the human body.
Many animals also harbour malarial strains, which worries him. “The idea of zoonotic disease is very important now, especially with COVID-19,” he said, pointing out that there is monkey malaria in Singapore.
As long as anopheles mosquitoes are still around, malaria could also return to other tropical regions of the developed world that have largely eradicated the disease, said researcher Nick White of the Mahidol Oxford Tropical Medicine Research Unit in Thailand.
In parts of the world, the malaria parasite has become resistant to the anti-malarial drug chloroquine, and alternative drugs such as artemisinin have been developed.
Artemisinin-based combination therapy is now used to prevent or mitigate drug-resistant malaria, but the reported evolution of strains that have a multi-drug resistance may hinder its efficacy.
With the cost and time involved in inventing more new drugs, Bifani feels that the best way forward for malarial treatment thus lies in the “proper management” of existing drugs.
WATCH: A bloody fight against mosquito-borne diseases (47:54)
BACTERIAL KILLERS BY DESIGN
Sometimes, however, chemistry gives new tools to disease hunters.
For example, Nanyang Technological University professor Mary Chan and her team have created a bacteria-attacking polymer from a chain of synthetic histidine molecules. Histidine is one of the body’s essential amino acids.
When the positively charged polymer comes into contact with negatively charged bacteria, it is attracted to the surface of the bacteria. Then it penetrates the bacteria’s respiratory pathway, traps the bacterial DNA and other essential molecules, and kills the bacteria.
“It’s hard for the bacteria to overcome all these multiple targets coming together,” said Chan. “Bacteria can change the charge, but not very easily because it’s a physical characteristic.”
The polymer can be programmed to break down into non-toxic parts after it does its work, and the body can release the smaller pieces easily.
It was successfully tested on a superbug in a laboratory in Singapore, and there are hopes that it could eventually become a new antibiotic. Its first use could be in diabetic wound dressings and as an anti-bacterial coating on medical devices.
“Bacteria will always be with us, but we need to kill them with something that’s sustainable and environmentally friendly,” said Chan. “Maybe polymer science is one of the few ways that you can do so.”
In the battle against drug-resistant bacteria, viruses and parasites, victory is not guaranteed. But as long as disease hunters come up with innovations, there is a chance of putting new and old illnesses to rest.
Watch the series Disease Hunters here.