Alternatives

We need new, breakthrough technologies or there may again come a time when an infected wound or an insect bite could mean death.

At the moment the alternative technologies to antibiotics are scarce. New, modified antibiotics only give us a very short breather; in most cases resistant bacteria pop up even before the market launch of the newest antibiotic.

What we actually need are antibacterial compounds that only target that one type of bacterium that makes us sick, leaving the rest of our microbiome alone. Ideally the bacterium will have very hard time in creating resistance against said compound.

  • Peptides
  • Phages
  • Endolysins
  • Artilysin®s

Peptides

Peptides
Peptides

Two well-known peptide antibiotics on the market are daptomycin and colistin. Daptomycin is the latest antibiotic (introduced in 2003) and is active on gram-positive organisms such as Staphylococci or Enterococci.

Colistin was introduced back in 1959, but has not been used because of its high nephrotoxicity. Today, colistin is one of the last resort antibiotics against highly resistant gram-negative bacteria such as Acinetobacter, Pseudomonas or Klebsiella.

Although not yet widely used, resistances have already emerged against both antimicrobial peptides. An American woman died because the infecting bacteria were resistant against all 26 antibiotics, including the last resort antibiotic colistin.

Other types of antimicrobial peptides (AMP) occur naturally in plants and mammals as a defence mechanism against bacteria or viruses. They have a broad spectrum and are positively charged in most cases.

The detailed mechanisms of AMPs are not yet fully understood. On the one hand, they eventually disrupt the bacterial membranes, leading to leakage or lysis due to the high inner osmotic pressure. On the other hand, AMPs may also interact with intracellular targets and interfere with the cellular metabolism.

A major concern of the usage of AMPs, besides the broad spectrum, is the development of a resistance, especially if AMPs, derived from the innate immune system were administered in the clinical routine. The frequent use of peptides derived from the innate immune system would select for resistant bacteria, which are even more dangerous because they would become resistant to our own immune system. These infections would then once again be treated with antibiotics, and you can probably already imagine what happens next:

the creation of the super-mega-monster-bug!

Andersson et al., 2016

Obviously peptides aren't the solution… so what else is out there?

Phage infecting a bacterium
Phage infecting a bacterium

Phages

“The enemy of my enemy is my friend”.

Phages are viruses that only attack bacteria. They are found everywhere bacteria exist, including the environment and even inside plants and mammals. They have been co-evolving with bacteria for billions of years. They are very selective and efficient. Lytic phages infect bacteria with their DNA, which reprograms the bacterium to produce new phages. Once enough phages are produced, the phages’ DNA initiates the production of a scissor, called endolysin, which cuts down the bacterial cell wall. The bacteria then burst and the phages are set free. They go on to the next bacterium and repeat the same process until all bacteria are gone. Then their work is done and they leave the body or wait for the next bacterium to infect.

This sounds great, right? Actually phages are fantastic and they are an excellent alternative to antibiotics:

1. They are highly selective, meaning they only kill the bacterium which causes the infection and leave the rest of the good commensal bacteria alone

2. They multiply within the bacteria until all bacteria are gone

3. They don´t attack the human body cells, so no side effects are to be expected here

4. They are quite easy to produce

Phage therapy is over 100 years old.

It started in 1917 with Felix d'Herelle in France and is still being practiced until today in Eastern Europe. In Tblisi, Georgia, the phage therapy institute called Eliava was founded by d´Herelle and George Eliava. Today, patients are still being treated successfully with phages at the Eliava Institute.

So why haven´t we heard so much about phages and why aren´t they available on the market yet?

There are a number of reasons.

1. First, we had antibiotics, and no-one asked for an alternative solution; Nobody was aware of the damage antibiotics would cause to our bodies

2. Second, the pharmaceutical industry was not really interested because phages are naturally occurring agents which can't exactly be patented, so no large profits are to be made.

3. Third, resistance formation against phages happens very fast. But this doesn't matter because for each bacterium there are 10 phages. So one just has to search for the right phage to combat the bacterium that causes the infection. That's the problem!

It's a problem in many ways for certain severe infections like Sepsis, or an acute lung infection for which there is simply no time to identify which strain is causing the infection. Further, an infection is often caused by several strains of the same species, which complicates the identification of the fitting phage mix.

4. Fourth, phages could eventually “pick up” DNA from a toxic bacterium and sometimes this act of “picking-up” will cause unwelcome effects, like the transformation of a relatively harmless E. coli into an EHEC

Phage therapy is a very personalized therapy. Approval of new pharmaceutical agents takes years and costs millions. Under the current approval procedure, it is impossible to approve phage therapy in a meaningful way by the regulatory authorities in Europe and the U.S.

Although vast amounts of experience have been gained with phage therapy in Eastern Europe, the collected data do not meet the Western standards of health care. Thus, these data are not of any help for an approval by the regulatory authorities in Europe and the U.S. At the moment, phage therapy is only available as a customized medical treatment when all other available agents (antibiotics) have failed, or by taking a trip to Tblisi, Georgia.

Lytic lifecycle of phages
Lytic lifecycle of phages
3D structure of phage SPN1S endolysin
3D structure of phage SPN1S endolysin from Salmonella typhimurium

Endolysins

From the phages we move on to Endolysins, a tool phages use to lyse bacterial cells from the inside after the phages have multiplied in the bacterium. Since the beginning of the 20th century, research on Endolysins has intensified. Endolysins work by cutting down the bacterial cell envelope, leading to lysis of the bacterium. Although phages digest the bacterial cell from the inside, the biotechnologically-produced Endolysin can also attack from the outside of the bacterium. This works particularly effectively on gram-positive bacteria such as Staphylococcus aureus or Enterococcus because their cell wall is accessible from the outside. In contrast, gram-negative bacteria feature an additional outer membrane layer, which shields the cell-wall.

Endolysins work fast, effectively and selectively, leaving the microbiome untouched. They work on highly antibiotic-resistant bacteria, as well as on sleeping (persistent) bacteria in chronic infections.

The efficacy of Endolysins has already been shown in diverse animal models and food applications.

Since there are 10 phages for every bacterium on this planet, and each phage carries the gene of an Endolysin, the implication is that for every bacterium on Earth there's an Endolysin to eliminate it.

Thus, Endolysins have great benefits:

  • They are selective and kill only the bacteria that cause the infection
  • They work on highly antibiotic-resistant and persistent bacteria
  • They attack a highly conserved cell structure, which makes it a hard job for the bacteria to develop resistance against Endolysins

As already mentioned, one major hurdle is the limitation of Endolysins to gram-positive bacteria only. The pan-resistant bacteria are gram-negative, such as Pseudomonas aeruginosa, Acinetobacter baumannii or Klebsiella pneumoniae!

So, Endolysins are great but they don't solve our problem!

This brings us to:

Artilysin®s

Artilysin®s are engineered antibacterial proteins
Artilysin®s are engineered antibacterial proteins

Artilysin®s are engineered antibacterial proteins. Their mechanism is principally based on that of Endolysins but it is improved and broadened by bioengineering. Due to an additional peptide moiety, Artilysin®s can pass the outer membrane of gram-negative bacteria and reach the cell wall. Subsequent destabilisation of the cell wall leads to lysis and the bacteria burst due to the high inner cell pressure (osmotic pressure). Imagine pushing a needle into a balloon with the inner pressure of a car tire. That's what Artilysin®s are doing with bacteria. Artilysin®s feature all positive properties of Endolysins but are also effective against the major problem-causing multi-resistant gram-negative bacteria. In some cases, Artilysin®s are even more efficient on gram-positive bacteria than Endolysins.

Artilysin®s have been under development since 2009 by various scientists around the world. These new molecules cover gram-positive and gram-negative bacteria and since they are based on Endolysins, for each bacterium these scientists theoretically can create an Artilysin®.

Artilysin®s completely fulfil our needs: they protect the microbiome because they work selectively; they work on all bacteria, even the multi-resistant ones – and it is very difficult for bacteria to develop a resistance against Artilysin®s because Artilysin®s attack a highly conserved cell structure.

Artilysin®s give us hope for a post-antibiotic era.

 

Artilysin® fast
Artilysin® selective

Taken together, what are our options?

There are three, very highly potent antibacterial agents which have the potential to replace today's antibiotics and work even better and more safely than antibiotics: Phages, Endolysins and Artilysin®s.

Phages

Phages are great, but they’ve not yet proved applicable for the masses, rather instead for personalized therapy. If worldwide small phage centres began to pop up, making a vast collection of phages available on a fast track, they could become a viable solution. At the moment, it is very hard to receive phage therapy – it depends on the regulatory authorities, politicians and the big pharmaceutical companies’ willingness to perform a paradigm shift.

Endolysins

Endolysins work well, but not against all bacteria, and in fact the bacteria that scare us the most are multi-resistant gram-negative bacteria which cannot be addressed by Endolysins.

Artilysin®s

But there are Artilysin®s, which feature the great benefits of Endolysins plus their spectrum can be broadened to combat all bacteria! In my eyes, this is the most intelligent way to move forward. These molecules can be applied for the masses, pharmaceutical companies may become profitable and regulatory authorities don’t need to be adapted. It will take a long time until resistance evolves (if at all) and until our microbiomes (or those of our children and grandchildren) can finally can recover from almost 100 years of antibiotics!

The following table gives an overview of alternatives for antibiotics. These alternative technologies have proven to be applicable for the treatment of bacterial infections and are rated according to the most relevant features necessary for a groundbreaking, future-orientated application.

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