You are browsing the archive for b-lactamases.

Bacterial apocalypse and the Cold War: the phage connection

15/05/2013 in Night science

The arms race turned against us in 2008. That year, an Indian citizen living in Stockholm was suffering from urinary tract pain, and even though he was treated with antibiotics bacteria seemed not to have any difficulties in resuming their growing. Later analysis determined that the bacterium, a Klebsiella pneumoniae strain, had acquired antibiotic resistance to b-lactamases thanks to a new enzyme activity, the so-called NMD-1 (New Delhi metallo-b-lactamase-1). This enzyme, present in gram-negative bacteria and transferable via plasmid, can disable carbapenems, a potent group of antibiotics that is normally used as the last defense line against highly resistant pathogens. Eventually this red line has gone down.

A high use of antibiotics leads to an increase of drug-resistan bacteria. It is interesting to highlight Spain position.

A high use of antibiotics leads to an increase in drug-resistant bacteria. It is interesting to highlight Spain's position.

Antibiotic resistance is not a new issue, but the main problem is that it skyrockets day by day, as can be extracted from Mac Sprenger’s words, the ECDC (European Center for Disease Control) Director, during the European Antibiotic Awareness Day event in the European Parliament: “Antibiotic resistance remains a serious threat to patient safety, reducing options for treatment and increasing lengths of hospital stay, as well as patient morbidity and mortality”, and from which it seems there is no light at the end of the tunnel: “Notwithstanding, we are seeing increasing multi-drug resistance and the emergence of resistance to last-line antibiotics in European hospitals which we must take urgent action to address.”. For example, only in the European Union 400.000 of patients suffering this kind of infections are reported every year.

How have we ended up in this situation? How have these resistances appeared? This is an evolution phenomenon, but instead of being produced by natural selection they have been supported by an artificial selection since patients and (especially) doctors have been the ones to blame for forwarding this outcome. As anyone with even the most rudimentary understanding of Darwinian processes knows, the use of antibiotics results in a selection process whereby hardy and drug-resistant microbes survive and breed; they’re simply adapting. When we take antibiotics we attack bacteria, either by not letting them to synthesize their protector wall (b-lactamases), inhibiting their protein synthesis capability or aiming other aspects of their physiology. But they can counterattack. For example, some mutations in their genomes as well as the up taking of genes from outside can help them to face powerful antibiotics. Every time we follow this therapy we eliminate the major part of the bacteria, however some survive to this event due to resistance acquisition. Think of a bacterium that has survived several times to these events: now it is almost invincible. This is a hallmark for the common nosocomial diseases (diseases that have contracted inside a hospital).

There are a huge number of difficult-to-eradicate pathogens like multi-drug resistant tuberculosis (MDR-TB), Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA) and more. Such is the problem that a new classification for these pathogens has recently (2011) been published. In the next table you can see it.

Table with non-susceptibility classification and comments for MDR (multidrug-resistant), XDR (extensively drug-resistant) and PDR (pandrug-resistant) bacteria.

Classification

Non-susceptibility to

Comments

MDR

At least 1 agent in 3 or more microbial categories

Dangerous

XDR

At least 1 agent in all microbial categories except 2 categories

Extremely dangerous

PDR

All agents in all antimicrobial categories

Apocalypse (good as a film plot)

 

Bacteria viruses can be appreciate easily in agar plates with previously grown bacteria.

Bacteria viruses can be appreciate easily as cell lysates in agar plates where bacteria have grown.

Increasing levels of antibiotic-resistant bacterial infections are now driving demand for novel therapeutic approaches. In cases where antibiotic options are limited because of a deficit in their development or nonexistent, the pressure for new agents is greatest. Among all the possible solution (new antibiotics, mixed therapies and so on) we will focus in this article on the administration of killing-bacteria viruses, also known as bacteriophages. Get ready for a curious story in the old-fashion “the enemies of my enemy are my friends”.

At the beginning (1920s) bacteriophages were sold at the pharmacies. Picture's copyright belongs to Dr James Soothill.

In the beginning (1920s) bacteriophages were sold at pharmacies. Picture's copyright belongs to Dr James Soothill.

Nowadays gene therapy is something we usually hear about and it involves a highly-specific treatment through unharmful viruses, so it also seems very rational to try to use bacteria viruses to eradicate pathogens, then why is this field not so popular? Let me tell you this fascinating story. Bacteriophages were discovered at the beginning of the 20th century by Frederick Twort and Felix d'Hérelle and since that moment a lot of research was focused on its application to treat microbial infection. Despite the apparent early successes and widespread application, these users did not understand the nature of these agents and their efficacy remained quite controversial. However, after the discovery of the antibiotics in 1941 the most advanced Western countries changed their mind: they will exploit this new source and put aside phage therapy, which was henceforth confined to Eastern countries that belonged to the former Soviet Union. World War II and the later Cold War did not do anything else but increasing this gap, this isolation between an antibiotic-based Western and phage-based Eastern (for sure they also used antibiotics, but phage use was very common) world. Eventually the possible use of bacteriophages to treat patients with bacterial infection was forgotten in the Western. And now, more than 60 years later we have seen how our antibiotic-based medicine has almost collapsed and the Western world will need the knowledge and help of countries like Russia or Georgia for the application of this very useful treatment.

Phage therapy can be very effective in certain conditions and has several advantages over antibiotics. For example, they do not develop secondary resistance, which is very common in antibiotics, or that they search for the specific bacteria and once they have destroyed them they do not reproduce anymore. Similarly to antibiotics, bacteria can also develop resistance to phages but it is a lot easier to generate new phages than new antibiotics. As bacteria evolve resistance, the relevant phages naturally evolve alongside so we can take advantage of their own arms race. When a "super bacterium" appears, then there is a "super phage" that can already attack it. Of course there are some disadvantages, like the necessity of finding a specific phage for the pathogen strain or the releasing of endotoxins by bacteria when there are being attacked.

 

Bacteriophages in action: thousands leaving host cell. Source: BBC news.

Bacteriophages in action: thousands leaving host cell. Source: BBC news.

Will phage uptake be a common therapy in the Western in a few years? This is difficult to foresee. Anyway, what is clear is that we have discovered (again!) a new way to eradicate the most lethal pathogens. We are likely to see its insertion in medicine as time goes by. Several results have demonstrated so far its effectiveness, but always combined with antibiotics.

So please, remember the take-home message about Darwinian evolution and (1) do not auto-medicate and (2) if you are about to use phage therapy ask for antibiotics too! :)

 

Further readings

[Phage therapy general info] http://en.wikipedia.org/wiki/Phage_therapy

[Issue tackled by BBC] http://www.bbc.co.uk/news/health-21799534

[Resistance classification] Magiorakos et al. (2012) Clin Microbiol Infect 18: 268–281

[More info about NDM-1] Lancet Infect Dis 2010; 10: 597

[Comments on phage therapy use] J Bone Joint Surg Am. 2013;95:e11(1-2)

[WHO antibiotic resistance webpage] http://www.who.int/mediacentre/factsheets/fs194/en/

[Straightforward article about bacteriophage therapy for treating wounds] Seth A.K. et al. (2013) Plastic and Reconstructive Surgery, 131:225-234