One of the major challenges facing modern medicine is the coming “post-antibiotic” era, in which we face numerous pathogens resistant to all available antibiotics. We are essentially engaged in an evolutionary war against pathogenic microbes, and by all accounts they are winning. We can delay the emergence of antibiotic resistance with best practices, but not prevent it entirely. We can also develop novel antibiotics, but the release of antibiotics using new mechanisms that can evade resistance has been extremely slow.
Clearly, while we do need to slow the emergence of resistance and develop new antibiotics, we also need to develop entirely new approaches to treating bacterial infections. I previously discussed here using viral phages as living weapons to attack infecting bacteria. This is a promising, but still experimental, approach.
Researchers are now also exploring the possibility of using bacteria themselves as weapons against bacterial infections. This may seem counterintuitive, likely because we tend to think of bacteria as germs, capable of causing infection. However, much less than 1% of all bacterial species can cause infections in humans (the estimate can vary widely, however, because the estimate of how many bacterial species exist varies considerably). Many bacterial species live in helpful symbiosis with humans, helping us digest our food and acting as part of our immune system (hence the whole notion of probiotics).
It is therefore not farfetched that we would be able to genetically engineer a bacterial species to help fight off antibiotic-resistant infections. This approach is also made more plausible by the rapid and incredible advances that are being made in genetic engineering technology. A recent study demonstrates the potential of this approach.
Victoria Garrido et al, publishing in Molecular Systems Biology, focused their sights on bacterial biofilms on implanted medical devices. Biofilms are notoriously antibiotic resistant, because they form sheets or films of bacteria that block access from either antibodies or antibiotics. They form an “exopolysaccharide matrix that adheres to a surface” and shields the bacteria within. A biofilm can be 1,000 times more resistant to an antibiotic than free-floating bacteria. There are multiple mechanisms of this resistance, including that biofilms can use efflux pumps to remove antibiotics from their environment. Often an implanted device that becomes colonized with a biofilm of bacteria simply has to be removed. Biofilms are also common, accounting for about 80% of bacterial infections.
There are many approaches to treating and preventing biofilms, including coating devices with surfaces resistant to adhesion or with embedded antibiotics, using electricity or ultrasound to break up biofilms so that antibiotics can get at them, or using enzymes or other antimicrobial proteins that dissolve the biofilm.
The researchers decided to use the enzyme approach, because while it can be effective it is limited by toxicity to host tissue. Their idea was to engineer a bacterial species to produce and release enzymes right on the biofilm. They decided to use Mycoplasma pneumoniae as the starting species, because it has a unique genetic code that limits horizontal gene transfer to other bacterial species. First they removed genes which give M. pneumonia the ability to cause infection, rendering it harmless. They then added genes to increase its ability to secrete enzymes. And finally they gave it the ability to produce two specific enzymes, one that is capable of dissolving biofilms and the other bacteriocidal against Staph aureus.
They tested their modified bacteria in vitro, and then both in vivo and ex vivo in mice (on catheters which developed S. aureus biofilms). They found that their attenuated M. pneumonia bacterium was safe and did not cause infection itself. Further, it was able to disrupt the biofilms and kill the S. aureus. The authors report that their treatment was 82% effective in removing the biofilms.
This is obviously a pre-clinical trial, but it is a compelling proof of concept. The researchers need to figure out how to mass produce their modified bacteria for further study. They are also planning on starting a clinical trial in 2023. Even in the best-case scenario we would likely not see such treatments in the clinic until the end of the decade. Often new technologies like this take 10-20 years to make their way into clinic use, and that’s if all goes well.
We are starting to see research into a number of “live” biological agents (viruses are only sort-of alive) to address the growing problem of antibiotic resistance and emerging infections. This is precisely what we need, entirely new approaches to fighting pathogens. The pharmacological approach may be playing itself out due to the emergence of resistance. Using viral phages and modified bacteria are promising technologies, made possible by incredible advances in genetic engineering.
These basic technologies also go beyond treating infections. The technology displayed in this research essentially is a bacterial delivery system – modified bacteria that are not capable of producing infection or transferring their genes to other bacteria, and can be used to produce and deliver protein payloads. Once a basic platform is perfected and proven safe, it can be modified for a long list of possible therapeutic interventions.
The one caveat to all of this is the fact that these therapeutic agents are self-replicating. The bar for proving safety is therefore incredibly high. We learned from our early attempts at using viral vectors for gene therapy that such agents can be risky. It took about 20 years longer than we initially thought, but eventually we developed safe viral vectors. It would therefore not surprise me if this research likewise takes longer than we currently think, or hope. We are not, however, in the same position we were in the 1990s. Biotechnology has advanced considerably, so it would also not surprise me if the time horizon for developing new genetically modified therapeutic agents is getting shorter.
Hopefully we’ll be unleashing these new microbial armies against human infections sooner rather than later.