The Latest Approach to Fighting ‘Superbugs’ – Synthesized Antibiotics and Antibacterial Polymers

The Threat Of Antibiotic Resistance

In a recently published article, we discussed how resistance to antibiotics is a growing threat to public health.

“Antimicrobial resistance (AMR) has caused 1.27 million deaths directly in 2019, with 1 in 5 of the victims a child under 5 years old. And 4.95 million people who died in 2019 suffered from drug-resistant infections, such as lower respiratory, bloodstream, and intra-abdominal infections.”

In that article, we saw how AI could help find new classes of antibiotics to beat bacteria resistance. We also discuss how viruses (bacteriophages) could be used in our article “Creating Living Antibiotics: BiomX vs Armata”.

As it stands, though, by 2050 the deaths from antibiotic resistance could amount to 10 million per year. This is partly due to the fact that the latest discovery of a new antibiotic class that reached the market was back in 1987.  But there are other possible ways we could manage to stop bacterial infections, including synthetic biology, and synthetic polymers.

Synthetic Proteins

A New Antibiotic?

An emergent field in biological research is creating and/or modifying proteins with amino acids that are not normally used in living cells. The central idea is that proteins can theoretically be built with hundreds of different amino acids.  The fact that only 20 amino acids are used by living organisms is just a quirk of Darwinian evolution.

This method can be used to modify compounds that have some interesting properties and make them a lot more potent.

This is what the team of Dr Ishwar Singh has done with a potential new antibiotic found in soil bacteria. It produces a molecule called teixobactin, which has been shown to kill Staphylococcus aureus, including antibiotic-resistant MRSA.

Source: Science Direct

Stopping Resistance From Appearing

Teixobactin might be less susceptible to developing resistance due to its mechanisms of action targeting lipids in the bacteria's membrane instead of more adaptable proteins. Still, concerns linger that large-scale clinical use of teixobactin could induce resistance.

A way to reduce this risk is to make the antibiotic much more powerful, reducing the number of bacteria able to survive it, and therefore adapt to it. Dr Singh's team has found that they can swap some of the teixobactin protein building blocks with cheaper and commercially available non-proteogenic amino acids.

This also increased the antibacterial potential by 16-32 folds.

Such spectacular results could open a whole new field of research in antibiotic development:

• Previously insufficiently active compounds could be re-engineered to create a whole new class of antibiotics.
• Antibiotics that suffer from widespread resistance could be modified to bypass the resistance mechanisms.
• New molecules could be created from scratch using synthetic protein designs, possibly with the use of AI to design and screen for antibacterial activity.

Synthetic Polymers

Universal Bacteria Killers

There are chemical effects against which bacteria do not develop a significant resistance. For example, pure alcohol can disinfect surfaces as well today as it did centuries ago.  This is because the antibacterial effect is linked to fundamental physical effects. In the case of alcohol, the ability of ethanol to destroy proteins' 3D configuration damages any lifeforms.

The issue with using such mechanisms in antibiotics is that being universal, they are highly toxic to human cells as well. This means they are generally not really usable inside a patient’s body in case of an infection.

Selective Synthetic Polymers

One universal chemical phenomenon that is toxic to bacterial cells is the disruption of the cell membranes. This can be achieved with cationic polymers, which destroy the chemical gradient between the inside and the outside of the bacteria's cell.

The problem in developing antibiotics with these molecules is that they are toxic to mammalian (i.e., human) cells.

A Texas A&M Team led by Dr. Quentin Michaudel thinks they have found a way to solve the problem. They discovered that you could modify the polymer to be harmful to bacteria but not (or at least much less) to mammalian cells.

“The placement of the cationic groups close to the core of the polymeric architecture rather than on appended side chains might improve both their bioactivity and selectivity for bacterial cells over mammalian cells.” – PNAS

More reliant on chemistry than biology, this process could be expanded to many other polymers with similar properties. In the long run, this might be one of the most promising venues for developing an antibacterial/antibiotic product that would not induce resistance in the long run.

Companies That Will Benefit From These Discoveries

Teixobactin has been licensed to the company Novobiotic. However, this is a privately held company, so it is not accessible to the large majority of investors.

Synthetic polymers are likely to be manufactured best by industrial giants with experience in complex polymer production, like BASF (BASFY) or Dow (DOW). But of course, this might depend on future patents and licensing from the universities and researchers that discovered the product. But in any case, in the long run, such antibiotics would fall off patents and become a chemical commodity, which will benefit chemical industry giants or generic drug manufacturers like  Sandoz Group AG (SDZNY)

If AI turns out to be useful to check early on for toxicity or find new compounds following the ideas of these discoveries around synthetic biology, the companies we highlighted previously, like Schrödinger, Inc. (SDGR), Exscientia (EXAI), and Recursion Pharmaceuticals (RXRX), Inc will likely be able to contribute as well.