Tuberculosis, or TB, is currently responsible for an estimated 1.5 million deaths every year, according to the World Health Organization, and although a number of effective treatments for the disease exist, resistance to these treatments is increasing at a rapid pace. Indeed, the WHO consider the spread of drug-resistant tuberculosis to be at ‘crisis levels’, following a dramatic rise in new cases back in 2013.

Tuberculosis DiagramOver the course of the last 40 years, treatment of TB has relied heavily on four main drugs, as well as a number of second-line medications, with the antibiotics rifampicin and isoniazid proving to be the most effective. However, with the rise of drug-resistant forms of the disease, and questions over the global effectiveness of the widely-utilised BCG vaccine, experts have warned that TB could result in as many as 75 million deaths by 2050.

Clearly, there is a strong need for new treatment options and researchers at Heinrich Heine University Dusseldorf in Germany are optimistic that they may have found the answer in the ocean. The team’s bio-prospecting research has identified organisms on a marine sponge found in Indonesia, which exhibit anti-TB activity. It is hoped therefore, that these compounds could be the source for the next generation of potent tuberculosis treatments.

Drug-Resistant Tuberculosis

The growing problem with TB drug-resistance was highlighted by the World Health Organization in 2014, after an estimated 480,000 new cases of multi-drug resistant tuberculosis (MDR-TB) infection were reported during the previous year. In simple terms, the problem arises when the bacteria which causes tuberculosis is able to develop a biological resistance to the drugs which are used to cure the disease.

Essentially, the crisis is a man-made problem, with two main causes:

  • Inadequate Treatment – Where a patient is given an insufficient dose to fully eliminate the bacteria from their body.Mycobacterium Tuberculosis
  • Lack of Compliance – Where a patient fails to take enough of the medication, and stops taking the medication early, or otherwise fails to follow instructions relating to dosage.

These two issues both mean that existing treatments are unable to fully eradicate the bacteria and what remains of the infection is able to develop a resistance to the drugs used. A major contributing factor to the problem is the fact that existing treatments for tuberculosis usually consist of multiple antibiotics being administered over a very long period of time.

Multiple drug-resistant TB is defined as a resistance to the two main treatments, isoniazid and rifampicin. When bacteria becomes resistant to at least three of the second-line treatments as well, it is classified as being extensively drug-resistant TB. Finally, totally drug-resistant TB refers to tuberculosis which is resistant to all current treatments and although far less common than other forms of drug-resistant TB, this poses the greatest threat.

New Treatment a Priority

While new-generation vaccinations, such as MVA85A and RBCG30, are in development, progression is slow and doubts have been raised over their effectiveness. The current Bacillus Calmette-Guérin (BCG) vaccine, meanwhile, is unreliable when it comes to protecting against TB in the lung; the most common form. Moreover, its effectiveness in general varies based on where the vaccine strain was grown, as well as other geographical influences.

As a result, the current priority lies with finding new treatment methods, which work differently to existing medicines, while delivering at least equivalent effectiveness. With their new marine bio-prospecting discovery, the team at Heinrich Heine University Düsseldorf are hopeful that they have taken the first big step towards achieving this.

Scientific Secrets of the Sea

CallyspongiaThe world’s oceans are home to various natural products, which are structurally unique in nature.

Scientific testing has shown that some of the compounds found in marine sponges, molluscs and bryozoans exhibit pronounced pharmacological activities and the discovery made by Dusseldorf-based researchers centres on a marine sponge called Callyspongia aerizusa, which is found in three different locations within Indonesia.

The team discovered that an extract from the sponge was active against Mycobacterium tuberculosis; the causative agent behind the vast majority of worldwide tuberculosis cases. This alerted them to the possibility that the sea could harbour a desperately needed new treatment for the disease.

From there, the extract was separated into 13 different fractions, all categorised as proline rich cyclic peptides, which were named Callyaerins A through to Callyaerin M.

Continued testing found that Callyaerin A was the most active against Mycobacterium tuberculosis, inhibiting 90% of bacterial isolates.

Cautious Optimism

“Our aim is to find a drug with a new mechanism of action,” researcher Georgios Daletos stated at BIOPROSP_15, a bioprospecting conference held earlier this year in Tromso, Norway. Daletos is optimistic about the potential of the compounds found in the ocean in Indonesia, although was quick to point out that many additional steps need to be taken before the discovery can be turned into a useful tuberculosis treatment.

Laboratory testing found that, when incubated with tuberculosis cells over a six week period, a level of resistance did develop, albeit at high concentrations of the drug and with the resistance forming at a fairly slow pace. Regardless, an important follow up step will be to determine exactly how this resistance develops.

Nonetheless, at a time when the spread of drug resistant tuberculosis is considered to have reached crisis point, and with current primary treatment methods having already been in circulation for around four decades, the discovery of sea-based organisms with anti-TB activity can be considered an exciting development in the fight against what remains one of the world’s most deadly and infectious diseases.