By Vidya Rajan, Columnist, The Times
Pathogens are organisms which cause disease, and we are regularly exposed to these pathogens through the food we eat, people we mingle with, animals we tend, and soil we dig.
Until the mid-twentieth century, vaccinations had been the preventive method. The discovery that weakened bacteria and viruses could activate the immune system to fight them at the next sighting caused terrified citizens to line up for the shot that could save them from horrible diseases such as smallpox, polio, tuberculosis and tetanus.
In the mid-twentieth century, the discovery of penicillin was heralded as something of a miracle – infections with many bacterial and fungal pathogens was no longer the death sentence they had once been (although viruses are not susceptible to antibiotics).
It set off a huge search for antibiotics, and the scientific discoveries and clinical miracles began to accrue until many people believed they lived in a post-pathogen world: where disease pestilences could be fought off with sophisticated drugs.
Then, evidence for antibiotic resistance in bacteria began showing in clinics. Previously easily defeated infections no longer yielded. Genetic sleuthing revealed that genes conferring bacterial resistance were being shared promiscuously. Soon, bacteria with appellations such as “MRSA” and “VRSA” started cropping up, their names tied to resistance to the antibiotics, methicillin and vancomycin, that had previously been the last resort – the big guns. And other pathogens which had never been seen before not only emerged, but began taking commercial flights and spreading around the world.
The purpose of antibiotics is to kill living things. Bio means life, and you can infer that the purpose of something that is “anti” is to oppose it. “Life” includes non-nucleated bacteria and archaea, as well as nucleated animals, plants, yeasts, and protists. Antibiotics interfere with biochemical processes including structure and function of the cells, such as cell wall synthesis, ribosome action, or DNA transcription. Antibiotics are often biochemical pathway- or organelle structure-specific. If one can target a pathway or structure that is interrupted by an antibiotic, that pathway or structure will be interfered with, no matter where it exists.
The USDA has been staring down a potential catastrophe in terms of antibiotic resistance due to their administration to farm animals in low doses to help animals quickly bulk up and also to suppress pathogens. The problem is that pathogens are developing resistance to those drugs, which are quickly becoming ineffective. In addition, it is hard to assess how much, if any, trickledown of the drugs administered to farm animals is creeping into human diets with possible negative effect.
For example, drugs given to bulk up livestock quickly can affect symbionts in our guts, fattening us in the same way. (The mechanism is simple. Microbiota in guts steal some of the energy in the food we eat. If we kill off the microbiota, then the energy accrues to the individual and causes additional weight gain.) Antibiotics against bacteria can also affect the symbiotic mitochondria within our cells, which are really bacteria that took up residence there in the earliest stages of evolution of animal cells. This is one of the reasons we feel tired if we are taking antibiotics against a bacterial infection.
Fungal infections can be even more problematic than bacteria because fungal cells are evolutionarily very similar to our own. Luckily fungi are distinguished structurally from animal cells because they have a chitin cell wall. Therefore most antifungals are targeted to destabilizing the cell wall, or are targeted to fungal-specific molecules such as ergosterol. The lethal chemical cross-activity is not limited to antibiotics. Cyanide salts are poisonous to all aerobic organisms because it interferes with a key shared enzyme – cytochrome C oxidase – in the mitochondrial electron transport chain which requires oxygen. On the other hand, anaerobic pathways of energy production may be slower, but they are also cyanide resistant.
Antivirals are not considered antibiotics because viruses are not considered to be “alive” since they do not have intrinsic energy production or metabolic pathways. They typically hijack another cell (bacterial, plant, protist or animal) to reproduce, either exploding the cell with runaway reproduction or integration into the host genome and budding out small numbers of viruses over a long period of time. To prevent replication of viruses without interfering with the cell’s replication, scientists have developed a slew of molecules that get introduced into the viral genome and disable it, turning out stunted viruses incapable of infection. This sort of treatment, particularly for viruses that take refuge in the host genome requires lifelong medication.
The search for new antibiotics is turning more interesting and definitely more creative. Besides the obvious methods of combining multiple antibiotics[1] during treatment, using artificial intelligence to screen the library of molecules that already exists for new bacterial targets[2] and designing vaccines that can use mRNA to target multiple variants such as of viral influenza,[3] scientists are turning to strategies that are unusual and truly “out-of-the-box”.
Here are a few:
- Using viruses to kill bacteria infecting the body. This is not a new strategy. It has been known for a long time that viruses are host-specific, and was developed in the mid-twentieth century in Eastern Europe and was even in the clinic as “phage therapy”. In the United States, this technique was recently used in the clinic after engineering viruses to specifically target the pathogenic antibiotic resistant bacterium to save the life of a young girl.[4]
- Turning the pathogens’ toxic molecules back on themselves. This is a brand-new strategy. Brice Felden, Director of the Bacterial Regulatory RNAs and Medicine laboratory in Rennes realized that a toxin produced by a bacterium had two separate functions – as a toxin and as an antibiotic. By using molecular tricks to separate the two functions, they found they could unleash the antibiotic without the toxic double whammy.
- Nano shells are traps of DNA with sugar moieties on the inside that can trap and hold multiple viruses.[5] These cages can be tweaked for emerging viruses and to filter outbreaks of old familiars by using click chemistry (Nobel Prize, 2022) to add surface antibodies.
“Fabulous!” you say. I do too. But to end, a real out-of-the-box hero – the common housefly. This humble pest, which is usually excoriated for transmitting disease, breaks down antibiotics in the environment to render the toxic sludge pouring out of factory farms less pestilential to the environment. [6] And so, hand in hand with our food production, pests and scientists we venture into the future, hauling with us our banes and our saviors.
Sometimes, they are the one and the same.
References
[1]. A Pietsch F, Heidrich G, Nordholt N, Schreiber F. Prevalent Synergy and Antagonism Among Antibiotics and Biocides in Pseudomonas aeruginosa. Front Microbiol. 2021 Feb 4;11:615618. doi: 10.3389/fmicb.2020.615618. PMID: 33613467; PMCID: PMC7889964.
[2]. Trefton, A. (2020) Artificial Intelligence yields new antibiotic. MIT News Office. https://news.mit.edu/2020/artificial-intelligence-identifies-new-antibiotic-0220
[3]. Rcheulishvili N, Papukashvili D, Liu C, Ji Y, He Y, Wang PG. Promising strategy for developing mRNA-based universal influenza virus vaccine for human population, poultry, and pigs- focus on the bigger picture. Front Immunol. 2022 Oct 17;13:1025884. doi: 10.3389/fimmu.2022.1025884. PMID: 36325349; PMCID: PMC9618703.
[4]. https://www.science.org/content/article/viruses-genetically-engineered-kill-bacteria-rescue-girl-antibiotic-resistant-infection
[5]. Monferrer A, Kretzmann JA, Sigl C, Sapelza P, Liedl A, Wittmann B, Dietz H. Broad-Spectrum Virus Trapping with Heparan Sulfate-Modified DNA Origami Shells. ACS Nano. 2022 Nov 2. doi: 10.1021/acsnano.1c11328. Epub ahead of print. PMID: 36323320.
[6]. Klein J. 2014 Nov 17. The fly — household pest, or environmental hero? Scienceline. [accessed 2022 Nov 29]. https://scienceline.org/2014/11/the-fly-household-pest-or-environmental-hero/.
