Antibiotic resistance has become our worst nightmare worldwide. In hospitals around the world, currently the common treatment for bacterial infections is antibiotics. However, some strains of bacteria have developed resistance against nearly all antibiotic drugs. Due to the lack of new drug innovation, bacterial infections caused by multidrug resistant bacteria have become deadly.
To overcome this crisis, scientists have designed a new antibiotic equivalent to ‘a poisoned arrow’ to target multidrug resistant bacteria.
Poisoned arrows are a traditional weapon used by native people around the world to hunt animals. A poisoned arrow pierces and wounds the target, so it can’t escape. Because it’s smeared with poison, this weapon makes the prey even more vulnerable. In short, this is an effective dual-threat weapon.
So, what happens when researchers create a drug with a dual-targeting action to kill bacteria?
What Makes Antibiotic Resistance a Crisis?
Antibiotic resistance is ongoing crisis when treating bacterial infections in the hospitals. Around the world, bacteria have developed antibiotic resistance rapidly and naturally, by mutations or genetic transfer among themselves.
Some resistant bacteria even gain another upgrade skill and become superbugs (or bacteria develop resistance against multiple antibiotics), so finding the cure for these bacterial infections is undeniably tough. To make things worse, the discovery of a new drug still can’t keep up with growing antibiotic resistance among bacteria.
Without discovery of a new drug, we may lose this battle against superbugs and it will cost us many more lives.
Priority List of Antibiotic Resistant Bacteria
To direct the focus of scientists who are interested in developing new antibiotics, the World Health Organization published a priority list of antibiotic resistant bacteria to target. The Centers for Disease Control and Prevention also issued a watch list of dangerous antibiotic-resistant bacteria and fungi. This watch list has three categories (urgent, serious, and concerning); based on how often the germs can kill, spread rapidly, and occur in the hospital and community.
If you want to learn more about the watch list, watch this video below.
Both organizations listed carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacer baumannii (all those germs are gram-negative bacteria). The first one infects the digestive tract, whereas the other two can invade surgical sites, blood stream, or the urinary tract. Without a doubt, these bacteria can be life threatening in the intensive care units, particularly for patients whose care needs ventilators and blood catheters.
Another antibiotic resistant strain from gram-negative bacteria on the lists is cephalosporin-resistant and fluoroquinolone-resistant Neisseria gonorrhea. This bacterial infection in women causes heart-breaking infertility and ectopic pregnancy. The latter is fatal for the fetus and it can also lead to the death of the mother.
Although not on the top priority, two strains of gram-positive bacteria on the lists (Vancomycin-resistant Enterococci/VRE and Methicilin-Resistant Staphylococcus aureus/MRSA) have affected healthcare costs in a significant way. These two bacteria are common contaminants on poultry meat and they easily spread throughout the community, nursing homes, and hospitals.
Before scientists start working on a new antibiotic to defeat antibiotic resistant bacteria, one thing to consider is whether the potential compound has a unique mode of action. For example, a new compound inhibiting penicillin-binding proteins may be ineffective as a potential new drug, because many superbugs are resistant to this mode of action.
Why Is It Hard to Discover New Antibiotics?
Discovering new antibiotics to defeat superbugs remains a tedious and challenging task to tackle, particularly for treating gram-negative bacteria. This is due to the outer membrane of gram-negative bacteria containing a thick lipopolysaccharide layer to block large and hydrophilic compounds from entering the cell (Breijyeh et al., 2020).
It’s also frustrating when a traditional way to screen natural compounds has been unsuccessful and produced no new drugs with alternative mechanisms against gram-negative bacteria in over 30 years (Lewis, 2020).
Ideally, creating a synthetic compound should overcome this limitation: by targeting a new mode of action or combining antibiotic mechanisms. However, it’s difficult to produce a synthetic compound with the ability to kill both groups of bacteria and still be safe for us.
The ‘Poison Arrow’ Drug Effective for Antibiotic Resistant Bacteria
To produce a new drug, researchers designed a synthetic compound (SCH-79797), aiming for both gram-positive and gram-negative bacteria (Martin II et al., 2020). The good news is the compound effectively slows down the growth of several antibiotic resistant bacteria (Enterococcus faecalis, N. gonorrhoeae, A. baumannii, and S. aureus strains). In addition, the researchers found no detectable resistance against this compound. The reason why this compound is effectively killing these bacteria: It has two completely different mechanisms of action.
Unique Dual-Threat Antibiotic
The study identified two targets of this new synthetic compound: bacterial cell membrane and folate metabolism (Martin II et al., 2020).
During the first action, this new compound punches holes on the cell membrane of bacteria. Bacterial cell membrane acts as a barrier to keep the contents inside the cell. When the barrier has holes, it causes the leakage of the cell contents and ions. This ends up killing the bacteria.
In addition to the first mechanism, this compound blocks the activity of dihydrofolate reductase inside. Dihydrofolate reductase is a key enzyme in the folate metabolism, mainly for the synthesis of glycine and purine. Consequently, it inhibits the synthesis of DNA and RNA, essential for a living cell.
After studying the mechanisms of this new compound, the next step is to answer the question of whether it is toxic for us.
Is the New Antibiotic Safe?
To test the safety of this potential antibiotic, the researchers used several mammalian cells (Martin II et al., 2020). The result of this test turned out to be disappointing. The effective doses of SCH-79797 for killing the bacteria inhibited the growths of some mammalian cells.
But, researchers included the derivative of SCH-79797 compound, Irresistin-16 (or IRS-16) and tested it on infected mammalian cells (Martin II et al., 2020). Remarkably, the study showed lower doses of Irresistin-16 (around 100-1000 times lower than the SCH-79797 doses) effectively killed the bacteria without affecting mammalian cells, and it worked well against the most resistant strain of N. gonnorhoeae in a mouse bacterial infection model.
Therefore, this study finally came out with a promising antibiotic drug candidate. Most importantly, it provides a new strategy—a dual-threat antibiotic—to defeat superbugs.
The Significance of This Study
Researchers successfully produced a poisoned arrow-like compound that perforates bacteria membrane and delivers a lethal ‘poison’ to kill multidrug resistant bacteria. This exciting innovation may inspire other scientists to discover more antibiotics with a new mechanism of action to solve antibiotic resistance crisis.
Bassetti, M., Peghin, M., Vena, A., & Giacobbe, D. R. (2019). Treatment of infections due to mdr gram-negative bacteria. Frontiers in medicine, 6.
Breijyeh, Z., Jubeh, B., & Karaman, R. (2020). Resistance of Gram-negative bacteria to current antibacterial agents and approaches to resolve it. Molecules, 25(6), 1340.
Brink, A. J. (2019). Epidemiology of carbapenem-resistant Gram-negative infections globally. Current opinion in infectious diseases, 32(6), 609-616.
Cillóniz, C., Dominedò, C., & Torres, A. (2019). Multidrug resistant gram-negative bacteria in community-acquired pneumonia. Critical Care, 23(1), 79.
DHFR – Dihydrofolate reductase – Homo sapiens (Human) – DHFR gene & protein. (n.d.). www.Uniprot.Org. https://www.uniprot.org/uniprot/P00374.
Lewis K. (2020). The Science of Antibiotic Discovery. Cell, 181(1), 29–45. https://doi.org/10.1016/j.cell.2020.02.056.
Lohner, K. (2009). New strategies for novel antibiotics: peptides targeting bacterial cell membranes. Gen Physiol Biophys, 28(2), 105-116. doi:10.4149/gpb_2009_02_105.
Martin II, J. K., Sheehan, J. P., Bratton, B. P., Moore, G. M., Mateus, A., Li, S. H.-J., . . . Savitski, M. M. (2020). A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance. Cell.
Princeton team develops ‘poisoned arrow’ to defeat antibiotic-resistant bacteria. (n.d.). Princeton University. Retrieved June 12, 2020, from https://www.princeton.edu/news/2020/06/03/princeton-team-develops-poisoned-arrow-defeat-antibiotic-resistant-bacteria.
Theuretzbacher, U. (2017). Global antimicrobial resistance in Gram-negative pathogens and clinical need. Current opinion in microbiology, 39, 106-112.