Natural antibiotics

by Markus Haastert and Anne-Kathrin Kuhlemann


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Background: antibiotics and the resistance problem
For the past few decades, the human life expectancy has increased significantly. That is the result of several achievements on the medical and pharmaceutical field, and a great example is the development of antibiotics and antifungals, which control such biological agents that cause diseases.
Besides medical care, such pharmaceuticals have been applied to several business sectors, among which are water treatment, agriculture, food preservation and oil and gas production. In fact, biocide compounds are currently found in everyday products such as mouth wash, deodorants, soaps, detergents, toys and chopsticks.
The antibiotic market has produced USD 42 billion in sales in 2009 globally, which represents 5% of the global pharmaceutical market. However, the market has seen better days. The average growth from 2005 to 2010 was 4%, which is considered a low growth rate. For 2016, demand is expected to be at USD 44.7 billion – not very high for a growth-spoilt industry.
One of the reasons for this economical change is that the frequent use of these substances has been causing a very dangerous problem, which is the antibiotic resistance, meaning that an ever increasing number of bacteria species are becoming resistant to the antibiotics that are available.
This phenomenon occurs because antibiotics kill most of the bacteria where they are applied, but each time, a few that are naturally resistant due to mutation survive. The ones that survived will, then, proliferate, generating a great number of antibiotic resistant bacteria. The speed in which such processes can occur is alarming. An experiment conducted by scientists of St. Jude Children’s Hospital, in Memphis, Tennesse (USA), was able to produce bugs resistant to triclosan, one of the main chemicals used to control bacteria, in only two days.
Besides, the use of antibiotics has side effects, given that it kills not only the harmful, but also the beneficial species of bacteria that live within the human organism, which are necessary for a number of body functions.
Another aspect regarding the presence of bacteria in the environment, is that they quickly proliferate into dense colonies, forming biofilms, slime-enclosed aggregates of cells that aggravate diseases and make bacteria resistant to antibiotics in an order of 10 to 1000 times more effectively. If bacterial biofilm is formed inside the human host, the infection will usually become untreatable, turning into a chronic state.

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There may be, however, another solution to the bacteria control problem. Peter Steinberg and Staffan Kjelleberg, both professors at the University of New South Wales (UNSW), noted while diving off the coast in Southern Australia that, despite the enormous amount of microorganisms in the ocean, a red seaweed (Delicea pulchra) was not colonized by bacteria.  As the seaweed itself was intact, they intuited that the solution found by those live beings wasn’t simply killing colonizers, since in that case the seaweed would end up killing itself as well. The researchers realized that, in fact, the seaweed was only blocking the communications amongst the bacteria, a process that is scientifically referred to as Quorum Sensing Inhibitor (QSI) chemistry. Quorum Sensing is the term used to refer to the means by which most disease causing bacteria mediate their biofilms. Therefore, unable to communicate with each other, the bacteria can’t coordinate, take over the host, nor produce biofilms.

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Innovation: bacterial control without antibiotics!
Steinberg and Kjelleberg were able to produce synthetic analogues of the inhibitor used by the seaweed which demonstrated high efficacy against a wide range of bacteria species, as well as inhibiting the growth of fungi. Tests have proven the product to be safe, and risk free of inducing bacterial resistance. This discovery really has the potential to be a game-changer regarding the way antibiotics are used in many fields such as medical treatment and medical devices, agriculture and food processing, industry, water treatment, etc. This could really mean, some years ahead, the end to bacterial resistance.

Along with their university, Steinberg and Kjelleberg created in 1999 a biotechnology company named Biosignal, dedicated to researching the QSI and its many applications. The intention of the company was to produce and commercialize a synthetic analogue to the substance found in the seaweed. However, even with the interest of private investors, the company struggled to do so. In 2010, Biosignal Ltd. was acquired by an entertainment company, and the products were discontinued.

Despite the potential, it seems that so far, companies have failed to take the innovation to the next step and actually develop and commercialize such products for practical applications. Cayman Chemical sells a number of products, mostly synthetic substances, which allegedly are Quorum Sensing Inhibitors. However, these products are for laboratory research only, not being indicated for any kind of human or veterinary diagnostic or treatment.
It seems one of the major efforts so far has been made by Unilever, which tested the seaweed extract to produce hygiene products. The company ran tests and confirmed its effectiveness for controlling body odor. However, it appears that product development has not gone further to date.

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Potential: a world without bacterial resistances
A great advantage of products that use the QSI principle, besides avoiding bacterial resistance, is that they can be applied to many fields, asides from the medical one.
The synthetic furanones which are responsible for the QSI effect, according to researches of the former Biosignal Ltd. Company, are effective on inanimate surfaces such as pipes, membranes and medical devices, as well as animate surfaces like lungs, skin and teeth. Hence, such products could be applied to diverse ends reducing maintenance costs, such as in pipelines, heating, ventilating, air conditioning systems, cleaning products, and water treatment. Another advantage is that these products are biodegradable, hence not causing pollution or toxicity, quite the opposite of traditional antibiotics.

The therapeutical potential of other QSI substances has been proven in other scientific research. A study observed that a meta-bromo-thiolactone compound was able to inhibit bacteria, preventing biofilm formation and protecting lung epithelial cells, as well as preventing the bacteria virulence factor expression. Also more specialized and complex applications are possible. Another group of scientists produced a patent, in 2012, for the use of QSI, as well as biofilm dispersing agents, for controlling biofilm-associated implantable medical related infections.
Regarding the development of QSI products, it seems a great step is ahead. Scientists have been investigating the presence of substances with this property in plant extracts, and they are believed to be toxicity free, though further long-term studies are still needed. Some examples of plants or parts of plants in which QS antagonists substances were found are garlic bulbs, vanilla beans, oranges, tea tree, rosemary, and pea exudates.
This discovery could make the development and commercialization of QSI products much easier, since it would only require the extraction of the substance from these sources, instead of developing a new synthetic substance entirely. Besides, similar procedures are widely used by pharmaceutical companies, whose products’ active principles are majorly obtained from plant matter.
The technical knowledge to use this revolutionary discovery is being produced every day. The key to a new world of bactericides relies on a company taking it to the next level.


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Maggot health care

Maggots for Wound Healing

by Markus Haastert and Anne Kathrin Kuhlemann


Background: The history of maggots

We begin our story in Porto Novo, the capital of Benin. There, Pater Godfrey Nzamujo founded the Songhai center in 1986. The Nigeria born priest opened the center as a food production site, in which he attempted to put all generated waste back into the system to generate new value from it. Plant biomass became substrate for mushrooms, sewage became biogas, remains from food processing became food for animals and slaughterhouse waste was used to breed maggots.
The priest even constructed a “fly-hotel” in order to produce millions of maggots. These can then be used as a protein-rich food for fish and chickens. In that way, waste is used to generate value.1 It would also be possible to produce maggots on the incredible amount of slaughterhouse waste which is generated annually. Estimations of the European Commission indicate that each year more than 16 million tons of non-edible animal side-products are produced in the European Union alone.2

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But maggots offer the potential for much more and have historically been used extensively in wound healing. Indeed, there have been relatively early observations that wounds which were colonized by maggots heal surprisingly well. In the 1930s, maggot-therapy was the state of the art in wound healing medicine. With the development of antibiotics, this method was however forgotten. In the 1990s however, when the first problems with bacterial resistances against antibiotics emerged, maggot-therapy found defenders once more. Also the Aborigines and other indigenous peoples are known to have used maggots to treat infected wounds.3


Innovation: Maggots for modern wound healing

There are many people in Europe who suffer from diseases which could be treated with maggots, the larvae of Lucilia Sericata – the common bluebottle or meat fly. According to doctors, more than three million people in Germany alone suffer from chronic wounds, with associated treatment costs of over five billion Euros.4 These people could be helped with a targeted maggot-therapy. Maggots have characteristics which help in the wound healing process. First, they clean the wound from infected tissue. And secondly, their excretions support the development of new tissue after the dead parts have been removed. Roughly 1,000 clinics in Europe and 300 in the US now regularly use maggots in their treatment of chronic wounds.5

The formerly widely spread believe that maggots only feed on dead tissue has been refuted.6 Thus, a continuous supervision by medicinal personnel is necessary when applying a maggot-therapy.
Side-effects of the therapy are practically non-existent when applied correctly. Mostly, patients have an itching feeling, if they feel anything at all. In case of an overdose, which means the use of too many maggots, healthy tissue can be affected which can lead to additional pain.7 In this case, the treatment has to be canceled straight away.

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To avoid having to put maggots directly into open wounds, British Professor Stephen Britland and his team developed a way to extract enzymes from the maggots to create a cream which can be applied on wounds.8 However, creams made from maggot-enzymes are still prohibited in Europe, as the technology is not yet advanced enough. In 2008, the first antibiotic on maggot-basis was developed. As about 20 maggots were needed to produce one drop of the antibiotic, the efficiency was still low.9

At the moment, maggots are mostly put in teabag-like sachets, which are then put on the wound to stay there for a few days. After removal, the animals are often more than two hundred times as big as before.10According to studies, the sachets however reduce the efficiency of the therapy significantly.11 Pills on maggot-basis are not an option, as the proteins will be digested before they can successfully begin the treatment – and since blood does not always circulate in the wounded area, which is part of the healing problem.12

Maggots also have the potential to fight the threateningly fast increase in resistances against antibiotics. In worst-case scenarios, which US scientists have calculated, annual costs of up to 55 billion US$ could develop as a result of such resistances, 20 billion for medicinal costs and 35 billion for lost productivity.13 Through the reduced application of antibiotics, maggot-therapy has the potential to slow down this process. Reliable numbers to what extent antibiotics can be replaced by the use of maggots are however not yet available.

The momentarily most popular opinion among doctors is that maggot-therapy is an excellent way to clean wounds. It is however not proven that wounds indeed heal more quickly than with conventional medicine. Usually, this therapy is used as the ultima ratio, when conventional methods have failed and surgeries are unsuccessful. Especially patients with chronically infected wounds have often benefited from maggot-therapy. Also patients with rheumatism and diabetes can benefit from it.

Potential: Saving lives and boosting the economy

Research on the medicinal use of maggots has just begun. As the focus for many years lay on fighting maggots as a vector of diseases, this field of medicine still has to catch up. At the moment, the potential of maggots to cure diseases such as a malaria or cancer is being evaluated. More research is essential to discover the full potential of maggots.14

Of special interest in this context is the possibility to implement this therapy in developing countries with insufficient medical services. Maggots could be bred decentrally in villages and would be available quickly in case of accidents. This could save numerous human lives. Infected wounds which lead to a sepsis are still a common cause of death, both in developed and developing countries.15

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Even better, if a simple technology could be found to extract the healing enzymes of the maggots, it would be possible to produce dearly needed medicine. A concentrated, locally produced cream from maggots, which were bred on waste and themselves serve as food for animals, could not only save human lives but also boost local economies.


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