The World Health Organization (WHO) is very clear: if urgent measures are not taken, the world is facing a post-antibiotic era in which many common infections will again be life-threatening.

What is a superbug? The term “superbug” is used to define those bacterial strains that are resistant to most of the antibiotics used these days.

Although it has been worsen in the last few years, resistance is not a new phenomenon. It is an inherent capacity of bacteria, which occurs naturally, and it can be delayed but not stopped. It is just an example of Darwin’s evolution theory, in real time. Bacteria adapt to the antimicrobials that we use to kill them, trying to guarantee their survival. In spite of being a natural phenomenon, which has always existed, in the last decades it has grown in an unusual way, becoming one of the most complex challenges for global health. We have been ignoring the warnings on the efficiency losses of some antibiotics for decades, due to a reckless and indiscriminate use in veterinary, agriculture and human health. And due to the unstoppable phenomenon of globalization the problem has been aggravated.

In 1928, the discovery of penicillin seemed to have forever erased the ghost of bacterial infections. Years later, while receiving the Nobel Prize, Alexander Fleming already warned us that the indiscriminate use of antibiotics would favor the appearance of resistant microorganisms. That prediction is nowadays already a dangerous reality. Superbugs are responsible for the death of more than 700,000 people each year (25,000 of them in Europe), and it is estimated that by 2050 that number will rise to 10 million. On that date, resistance to antibiotics will kill more people than cancer or cardiovascular diseases. In order to stop this process, it is necessary the coordinated and global action of every government, prevention measures and the discovery of new drugs.

Reckless use and abuse of antibiotics 

Among the measures to end the indiscriminate use of antibiotics, the European Union banned the sale of them without medical prescription more than 15 years ago, and in 2006 the integration of antibiotics as a food supplement in animal feed. However, years later, these measures seem not to work, mostly due to globalization. These resolutions are useless if they are only applied in some countries. In the USA, antibiotics are still being used for fattening of animals, as well as in many developing countries, which are not willing to lose productivity in a high demand for meat market. Also, the indiscriminate use of antibiotics in feed for decades, has meant the inclusion of the same to the soils, from where they are filtered to the aquifers, reaching lakes, rivers and finally the water network for human use. The result is that we are in contact with antibiotics, and even with superbugs, every day, therefore we are becoming potential vectors of infection. We need a strategy to slow down the fast appearance of new resistances, as well as new tools to fight with those we currently have. Next, we briefly summarize some experimental approaches to face this problem.

New antibiotics

The search for new antimicrobials has been slowing down for years and more than 3 decades have passed since the last completely new antibiotic was launched to the market (Daptomycin, 1987). It is not profitable for the pharmaceutical industry to invest time and money in the discovery of new antimicrobials, which may cease to be effective in a few years due to the appearance of new resistances, with no time to recover the investment. In the search for antagonistic microorganisms to superbugs, it is worth highlighting the recent discovery of a bacterium (Streptomyces sp. Myrophorea), isolated from a soil sample of what is known as Boho Highlands, in Northern Ireland, which is able to inhibit the growth of 4 of the most dangerous multi-resistant bacteria. Strangely enough, these soils have been used in traditional medicine, for their healing properties, since ancient times. Currently, we are working on the isolation and identification of the metabolites responsible for this activity.

 

Biomar Microbial Technologies has had among its objectives the discovery of new antibiotics since its creation. And in the last few years, in cooperation with ABAC Therapeutics, more specifically the search for specific antibiotics against multi-resistant bacteria. We know the targets, and we have some of the largest collections of marine microorganisms, extracts and pure compounds, which we consider a great starting point to identify new molecules with anti-bacterial activity.

Vaccines

The search for specific viruses against resistant bacteria using the phagotherapy technique is another alternative. This research area, which has been known for more than a century, was abandoned precisely because of the appearance of antibiotics. However, this it is being restored, so it is possible that in the next few years a dose of virus might be the cure for some infections.

Nanoparticles

Currently, nanotechnology allows us to create nanostructures of inorganic origin, such as silica or different metals. Using antibiotics bonded to metal nanoparticles as bactericides can be highly effective because the bacteria are well adapted to develop immunity to current antibiotics but metal nanoparticles are a new concept for them and do not recognize them as a threat.

New strategies

A new strategy against superbugs has recently been published in the journal Cell, by a group of researchers from the National Center for Biotechnology of the CSIC, led by Dr. Daniel López. They have discovered that the surface of the bacterial membrane is not homogeneous but has microdomains, called lipid rafts, which are key to the formation of protein complexes related to antibiotic resistance. They have designed a strategy to break those rafts down using statins (a common drug in the treatment of hypercholesterolemia), resulting in non-resistant bacteria, which can be treated with conventional antibiotics. This research is being currently carried out with Staphylococcus aureus MRSA, one of the deadliest strains in the hospital setting, with great results in the in vivo tests in mice. In addition, eliminating these microdomains lacks of biological pressure for the survival of the bacterium, which minimizes the risk of the appearance of new resistances.

To sum it up, superbugs are among us and they have come to stay. We have a lot of work to do and little time, especially considering that a bacterium can grow in 20 minutes, while launching a new antibiotic to the market takes between 10 and 15 years on average.

More info:

  1. Antimicrobial resistance: global report on surveillance, 2014
  2. Antibiotic resistance is ancient. Nature, 477, 457-461, 2011
  3. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. Review on Antimicrobial Resistance, 2014
  4. A Novel Alkaliphilic StreptomycesInhibits ESKAPE Pathogens. Frontiers of Microbiology, October 2018, Vol. 9, Article 2458
  5. Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World J Gastrointest Pharmacol Ther, 2017 8(3): 162–173
  6. Nanomaterials for alternative antibacterial therapy. J. Nanomedicine, 2017, 12, 8211-8225
  7. Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance. Cell 171, 1354–1367, November 30, 2017

 

José María Sánchez López

Head of Natural Products Chemistry Department