water pollution: beta-cyclodextrin polymer

What is the story of beta-cyclodextrin polymer?

Polar organic molecules, such as bisphenol A, are major sources of water pollution and hence filter materials are designed intentionally to filter out such organic molecules.  It is of greater research interest to figure out how to remove polar organic molecules as compared to non-polar organic molecules from water because polar organic molecules dissolve to a certain extent in water. Hence, a simple filtration system to remove solid from liquid does not work. More science has to be involved in designing a filtration system to remove polar organic molecules from water. A recent study has found that beta-cyclodextrin polymer can actually filter out polar organic molecules much more effectively and faster as compared to current water filters, e.g. activated charcoal. Not only does beta-cyclodextrin polymer work better, it is arguably cheaper to manufacture as compared to current technologies. As of now, the cost of making beta-cyclodextrin polymers is half of what is required for making activated charcoal. This means greater accessibility to good water filtration systems.

bisphenol a
Structure of bisphenol A
Illustration of the new beta-cyclodextrin-based water filter technology (Photo credits: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature16185.html)

How does beta-cyclodextrin polymer work?

beta-cyclodextrin is made up of 7 of the sugar rings  in a cyclic arrangement. The sugar ring itself consists of 6 carbon atoms. Even though the structure might seem complicated, the synthesis is quite straightforward. By treating starch with certain enzymes, beta-cyclodextrin can be produced with relative ease.

Structure of beta-cyclodextrin (the sugar ring is circled in red)

What the researchers did in the water filter study was to link each of the 7 sugar rings in beta-cyclodextrin by an aromatic compound, tetrafluoroterephthalonitrile (structure shown in red in the 1st diagram). By doing so, the scientists ensure that the cyclic structure is both rigid and porous. It is important that the structure is porous so as to maximize absorbent performance. After all, what is the point of a water filtration system if the water can’t pass through?

Where are we going with beta-cyclodextrin polymer?

Will beta-cyclodextrin polymer work or will it just remain as a novel idea? Besides effectiveness and cost of production, another really important factor here is safety. It is important that we are sure that the water that passes through the beta-cyclodextrin polymer is safe for drinking – not just for the moment but over time as well. What makes beta-cyclodextrin very promising is the fact that it is made up of sugar subunits and sugar is definitely safe for consumption. However, the same cannot be said about tetrafluoroterephthalonitrile. The chemical tetrafluoroterephthalonitrile itself is poisonous and should not be ingested.  Will the beta-cylodextrin polymer degrade over time after prolonged usage? Will tetrafluoroterephthalonitrile find its way to the filtered water? Further research will tell us.

malaria, pharmaceutical companies

Martin Shkreli: pyrimethamine

What is the story of pyrimethamine?

Martin Shkreli, the CEO of Turing Pharmaceuticals, is arguably the most hated man in the US right now. His company bought the exclusive rights to sell Daraprim, the brand name for the generic drug pyrimethamine, and raised the price of the drug from USD$13.50/ tablet to USD$750/ tablet.  Pyrimethamine is commonly used to treat a parasitic infection called toxoplasmosis that can be life-threatening for patients with impaired immune system, such as HIV-positive patients. Besides toxoplasmosis, pyrimethamine is also used to treat malaria. Pyrimethamine is on the list of World Health Organization’s List of Essential Medicines which means that it is considered a very important drug in any healthcare system. In spite of its status as an essential medicine, Martin Shkreli argued that the drug is rarely used in the US  so the price hike would not affect the healthcare system too much. He claimed that the extra profit that Turing Pharmaceuticals get from the sales of the drug will be channeled to the research and development of new and better drugs to treat toxoplasmosis. There is something that does not quite add up here. R & D in the pharmaceutical industry needs big money; if the price hike is not going to affect the healthcare system too much, then where does the big money come from? The truth is some individuals are going to incur huge costs to put Turing Pharmaceuticals in the position to conduct any R & D of new drugs to treat toxoplasmosis. Is that fair? Is it time for us to limit the market forces in the pharmaceutical industry?

Structure of pyrimethamine

How does pyrimethamine work?

Moral questions aside, now let’s think about chemistry. Pyrimethamine inhibits DNA synthesis by blocking the activity of dihydrofolate reductase of plasmodia. What is smart about pyrimethamine is that it is selective; it binds to the dihydrofolate reductase enzyme of plasmodia about 2000 times stronger than the same enzyme of the human host. Even though the enzymes in plasmodia and humans perform the same function, they don’t look the same. The enzyme in plasmodia has a molecular weight of 200, 000, about 10 x larger than the enzyme in humans. This selective toxicity property is the reason why pyrimethamine can kill the parasite without killing the host.

Where are we going with pyrimethamine?

The medical community feared that the price hike on Daraprim (brand name for pyrimethamine) will result in patients having to switch to less effective but cheaper drugs. However, that is unlikely to happen. In fact, the price hike will not be long. This is because pyrimethamine is not a patented drug; it is a generic drug. Patents are there to reward innovation so when a drug company creates a new drug to treat a disease,  the company can patent its innovation (usually for a period of 10 years) so that they can make economic gains on that new drug. On the other hand, when a drug becomes generic, as in the case of the 62 year old pyrimethamine, other drug companies can legally make and sell pyrimethamine as well. What they cannot do is to sell pyrimethamine under the brand name of Daraprim because Turing Pharmaceuticals has the exclusive rights to the name Daraprim. However, they can sell the drug using their own brand names. That is what is happening right now. CVS Health Corp , the No. 2 U.S. drug benefit manager, told the media that it can provide an alternative to Daraprim that is compounded by Avella Specialty Pharmacy, at a price of USD$30 per 30 pills. In this era when drug companies are under-fired for selling new, more effective therapies at high-sky prices, perhaps corporate responsibility is arguably more important than immediate economic gains.

cosmetics, redox

TCM: arsenic trioxide

What is the story of arsenic trioxide?

Recently, it has been reported that a traditional Chinese medicine (TCM) product, which claims to treat eczema, was found to contain dangerously high levels of arsenic.The product in question is the TCM Reciple Licozen Ointment. Eczema is a medical condition in which some patches of skin become rough and inflamed with blisters.  Ironically, arsenic-containing compounds can cause skin irritations, rashes and blisters according to HSA, further aggravating the skin inflammation. To make things worse, prolonged exposure to products containing arsenic may result in arsenic poisoning, which manifests itself in a wide range of symptoms such as vomitting, abdominal pain, diarrhoea, heart-related problems, breathing difficulties and numbness of the limbs. In TCM, the arsenic-containing compound is usually arsenic trioxide which originates from arsenolite (砒石).

Image of TCM product containing high levels of arsenic

How does arsenic trioxide work?

Arsenic trioxide is a poison and it kills cells by causing oxidative stress and chromosomal aberrations to the cells. The oxidation state of arsenic in arsenic trioxide is +3 (trivalent). Trivalent arsenic is known to be more toxic than the pentavalent arsenic (oxidation state = +5). The reason for the differential toxicity is that a trivalent arsenic binds to thiol group found in a wide variety of proteins far more readily than a pentavalent arsenic.

Structure of thiol group


Where are we going with arsenic trioxide?

The toxicity of arsenic trioxide is exploited to kill parasites. It has been established that some microbes might cause eczema. Hence, the rationale of having arsenic trioxide in a product that treats eczema is that this toxic compound could kill the microbes that cause eczema. However, eczema is a very complex medical condition and besides microbes, many other triggers, such as allergens, irritants and food, might cause eczema as well. Products using arsenic trioxide as an active ingredient may not be effective when eczema is not caused by microbes. How do you know if your particular case of eczema is caused primarily by microbes? You don’t know for sure so it is best to avoid products that possess highly toxic ingredients and may not be suitable for your condition.

Arsenic trioxide is also used to kill cancer cells. Currently, the combination of arsenic trioxide and all trans retinoic acid have been approved by the Food and Drug Administration in the US for the treatment of  acute promyelocytic leukemia It is highly unlikely that arsenic trioxide will become a mainstay of chemotherapy. This is because arsenic trioxide, like other heavy metal chemotherapy drugs (e.g. cisplatin), is non-specific and it will very likely cause a lot of adverse side effects to the patients. The current trend in chemotherapy drugs favours organic compounds that are designed to specifically kill cancer cells.


Group B streptococcus: Benzylpenicillin

What is the story of benzylpenicillin?

Benzylpenicillin, or penicillin G, is an antibiotic given either intravenously or intramuscularly to treat some form of bacterial infection. Doctors prefer to use the intravenous form of benzylpenicillin to treat patients who have contracted Group B streptococcus (GBS) bacterial infection. Globally, GBS infection is the leading cause of morbidity as well as mortality among newborns. Recently, in Singapore, not only does GBS infection affect newborns adversely, some adults have also fallen very ill after contracting a specific strain of GBS infection. GBS infections are allegedly linked to the consumption of raw fish in some cases. The deadly strain of GBS bacteria found in raw fish is the Sequence Type 283 (ST283). The Ministry of Health in Singapore has reported that “it had been notified of 355 cases of GBS since the start of the year and about 150 of the cases were linked to the consumption of the Chinese style raw fish dishes.” Can benzylpenicillin resolve the crisis for Singapore?

Structure of benzylpenicillin
image of raw fish
Image of raw fish dish in Singapore (Photo credits: http://www.straitstimes.com/singapore/health/raw-fish-and-gbs-infection-7-questions-about-the-bacteria-answered)

How does benzylpenicillin work?

Benzylpenicillin, similar to other forms of penicillin, inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs). Benzylpenicillin does not work equally well on all kinds of bacteria. Benzylpenicillin kills susceptible, gram-positive bacteria and it has limited efficacy on gram-negative bacteria. What are the differences between gram-positive and gram-negative bacteria? Structurally, gram-positive bacteria has a thick layer of peptidoglycan while gram-negative bacteria only has a thin band of peptidoglycan. Another structural difference is that gram-negative bacteria has an outer membrane which is made up of phospholipids. Gram-negative bacteria is known to be more resistant to antibiotics as compared to gram-positive bacteria.

Difference between gram-positive and gram-negative bacteria (Photo credits: http://www.dreamstime.com/stock-illustration-gram-positive-gram-negative-bacteria-difference-bacterial-image45337024)

Where are we going with benzylpenicillin?

Although gram-positive bacteria, such as GBS, are less resistant to antibiotics, it does not mean that it will not develop resistance towards antibiotics. The problem with just using penicillin-based antibiotics to treat GBS is that GBS might develop resistance. Hence, it is imperative to use an arsenal of antibiotics with different mode of actions to prevent the development of resistance. Apart from benzylpenicillin, other antibiotics that have been effective against GBS are ampicillin and cefazolin.

cosmetics, redox

cosmetic product: hydroquinone and tretinoin

What is the story of hydroquinone and tretinoin?

Besides thimerosal, high levels of hydroquinone and tretinoin are also found in the questionable cosmetic product that was investigated by the Health Science Authority in Singapore just last month. Recall that the questionable cosmetic product is claimed to have skin whitening effects. Hydroquinone is a small aromatic organic compound, more precisely a phenol. On the other hand, tretinoin is the carboxylic acid version of vitamin A. HSA claimed that hydroquinone and tretinoin may cause increased sensitivity of the skin to sunlight and cause users to get sunburned more easily so consumers of such products need to avoid sun exposure.

Structure of hydroquinone
Structure of tretinoin
face lift
Image of the questionable cosmetic product (Photo credits: http://www.ebay.com/itm/Meiyong-Super-Extra-Whitening-Cream-Seaweed-Face-lift-natural-Algae-/360479332033)

How do hydroquinone and tretinoin work?

I will start with tretinoin. According to some studies, tretinoin irritates the skin and causes old cells to die and new cells to multiply, essentially increasing the turnover of cells. This is how “miracle creams” containing tretinoin treat pimples and reduce areas of darkened skin. That is what you are doing to your skin when you put that cream on it.

Hydroquinone, on the other hand, inhibits the synthesis of melanin – the skin pigment that gives the skin the dark colouration. How does hydroquinone do that? The synthesis of melanin requires an oxidation step to make dopaquinone from dopa. Phenol oxidases catalyze the oxidation process. Hydroquinone is essentially a reducing agent which inhibits the oxidation process. Imagine: electrons are removed from dopa during the oxidation process. Hydroquinone essentially donates its own electrons back to dopa, undoing the oxidizing efforts of phenol oxidases. Hydroquinone itself is oxidised into benzoquinone in the process of donating its own electrons to dopa. By preventing the synthesis of melanin, hydroquinone prevents the skin from getting darker.

melanin synthesis pathway
melanin synthesis pathway (photo credits: http://web.mst.edu/~microbio/BIO221_2009/images_2009/cryptococcus-3.gif)
hydroquinone as a reducing agent
hydroquinone is oxidised to give benzoquinone

Where are we going with hydroquinone and tretinoin?

Both hydroquinone and tretinoin increase the skin’s sensitivity to sun so either 1) apply lots of sunscreen before going out or 2) avoid sun exposure all together. After all, if you want to have a fair skin, you ought to be conscious of sun exposure to your skin. My question to the companies making cosmetic products is: are the consumers aware that they have to reduce direct sun exposure to their skins after applying the whitening products? How much do you know about what you are applying onto your skin?

cosmetics, organometallic

cosmetic product: thimerosal

What is the story of thimerosal?

Just last week, the Health Science Authority (HSA) in Singapore reported that a face cream product sold in Singapore contained very high levels of toxic chemicals, including a mercury-based substance – thimerosal. The face cream product in question is “Meiyong Super Whitening Extra Whitening & Face Lift Advanced Super Revitalizer (Cream) Whitening Formula And Face Lift”. Quite a cumbersome and long name, I know.  Mercury (chemical formula: Hg) is found in the transition metal block, otherwise known as d-block, and it is the only metal that exists as liquid at room temperature. The use of mercury in cosmetic products has been around for a long time as the Romans commonly used it in their cosmetics. It was only in 1974 that the use of mercury in cosmetics became “strictly regulated” by the Food Development Authority (FDA) in the US.  In thimerosal (an organometallic compound), mercury has a coordination number of 2 and is bound to a thiol ligand and an ethyl ligand. HSA claimed that mercury-based substance such as thimerosal may cause rashes, skin irritation and blotchiness, and can be absorbed through the skin to cause numbness, dizziness and headaches.  Furthermore, chronic exposure to high levels of mercury may also affect the kidneys.

Structure of thimerosal
face lift
Image of the questionable cosmetic product (Photo credits: http://www.ebay.com/itm/Meiyong-Super-Extra-Whitening-Cream-Seaweed-Face-lift-natural-Algae-/360479332033)

How does mercury work?

Thimerosal acts as a preservative in cosmetics by inhibiting the growth of bacteria and fungi that could potentially damage the products.  Imagine seeing fungi growing on your skin care cream! Besides being used as a preservative in cosmetics, thimerosal is also used as a preservative in vaccines and skin test antigens. Thimerosal is found in especially high concentrations in skin lightening creams.

Where are we going with regulation of mercury in cosmetic products?

The regulation of mercury-containing compounds in cosmetics is not a straightforward process. Some companies argue that it is not possible to replace thimerosal with other kinds of preservatives in their products. Beside skin lightening cream,  cosmetic products that are often in question are eye make-up products such as mascara and eyelash make-up. The problem is that companies want to produce eye make-up products with long shelf-life, such as 5 years, and they have to put preservatives in their products to keep them on the shelves for such a long time. I think I can understand their commercial objectives but what really annoys me is that consumers probably do not know that products with long shelf-life most likely contain mercury-based compounds and these compounds will most likely cause health problems to the consumers in the long run. Public awareness about the science in the day-to-day products that we use needs to be improved.

antibiotics, food additives

Feed additives: colistin

What is the story of colistin?

Colistin is made up of cyclic polypeptides (10 peptide bonds) and it is an antibiotic produced by certain strains of Paenibacillus polymyxa var. colistinus.  Antibiotics kill bacteria but at the same time, antibiotics are also the very agents that drive antibiotics-resistance in bacteria. For instance, antibiotics may kill 99 % of bacteria in the culture but the 1 % that somehow survive the antibiotics’ assault further proliferate and dominate the culture. That is evolution in microbiology. Colistin is a decades-old drug that fell out of use because of its nephrotoxicity (toxicity to the kidneys). Currently, it serves as one of the last-resort antibiotics to kill multi-drug resistant (MDR) bacterial strains. Recently, it was reported that bacteria can also gain resistance to colistin in both animals and humans. How did that happen? While the doctors carefully refrain from using colistin so as not to put the selective pressure on bacteria to create colistin-resistant super bacteria, the farmers are not as careful. Farmers, particularly the Chinese farmers, use colistin as a feed additive to feed the pigs. Globally, The Lancet  estimates agriculture purchases around 12,000 tonnes of colistin per year. Colistin-resistant super bacteria are created in the guts of the pigs and over time, these super bacteria are transferred to the humans who eat the pigs. 

Structure of colistin
Image of pig reared in China (Photo credits: http://phenomena.nationalgeographic.com/2015/11/21/mcr-gene-colistin/)

How does colistin work?

Colistin contains alkyl groups and peptide bonds which make it hydrophobic and hydrophilic respectively. The cell membrane of the bacteria is also both hydrophobic and hydrophilic (note: the term for something that is both hydrophobic and hydrophilic is amphiphilic). The cell membrane is made up of phospholipids (see image below) which have hydrophilic phosphate heads and hydrophobic hydrocarbon tails. When colistin is administered, colistin essentially interacts with the phospholipids since its degree of hydrophobicity is very similar to that of phospholipids. The interaction between colistin and the phospholipids then disrupts the cell membrane and this in turn kills the bacterial cell, similar to how detergents work to disrupt membranes.

Image of phospholipids in the cell membrane (photo credits: https://en.wikipedia.org/wiki/Phospholipid)

Where are we going with colistin?

The Ministry of Agriculture in China has decided to take swift actions and closely monitor the use of colistin in animal feed. Beside China, the  Central Veterinary Institute in The Netherlands has also said that it will put in the effort to control the spread of colistin resistance. Some has called for a ban on colistin from animal feed. But is this a case of too little, too late? Did we already lose one of our last-resort artillery against bacteria to ignorant use of colistin? Only time will tell us.