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Since the discovery of penicillin in 1928 by Sir Alexander Fleming, antibiotics have transformed human health by saving millions of lives and alleviating much human misery. However, scientists soon discovered that massive usage of antibiotics in clinical practices and commercial animal husbandry contributed to the rise of bacterial “superbugs” that are resistant to the drugs designed to kill them (1,2). Furthermore, researchers report that, for a bacterial pathogen already resistant to an antibiotic, prolonged exposure to that antibiotic not only boosts its ability to retain its resistance genes, but also makes the pathogen readily transform into a dangerous, multidrug-resistant strain (3). Hence, antibiotic resistance has become a major health concern around the world.

To understand how microbial resistance is developed, we must first understand the modes of actions of antibiotics. The most common mechanism is interference with microbial ability to make cell walls. Antibiotics, such as penicillin and its derivatives can inactivate key bacterial enzymes (peptidases) that synthesize the rigid cellular walls, leading to the loss of structural support and collapse of bacterial cells. Another common mechanism--used by drugs including chloramphenicols and tetracycline--is inhibition of bacterial protein synthesis. The bacterial ribosome--the location for protein synthesis--is one of the main targets of antibiotics, with most clinically used antibiotics preventing either the binding of tRNA or the formation of peptide bonds (8). The third mechanism is interference with bacterial genetic synthesis or operation (1).  

Among the billions of germs of any infection, a few somehow survive and replicate due to insufficient dosage or misuse of antibiotics, forming a new “antibiotic resistant” infection. However, antibiotics do not induce resistance, as once thought, but rather their inadequate use lead to an evolutionary mechanism wherein they merely serve to create the conditions that favor the outgrowth of preexisting antibiotic-resistant organisms (1).

In 2017, the World Health Organization (WHO) published a list of antibiotic-resistant priority pathogens that present a great threat to humans. The majority of the WHO list is Gram-negative bacterial pathogens, including Acinetobacter baumannii and Pseudomonas aeruginosa, which are categorized as critical priority. Gram-positive bacteria consist of a cytoplasmic membrane surrounded by a tough and rigid cell wall. In contrast, Gram-negative bacteria is surrounded by a second membrane called outer membrane (OM), which contains outer membrane proteins such as porins which allow the passage of small molecules like amino acids and hydrophilic antibiotics (5). The presence of OM in Gram-negative bacteria confers enhanced ability to regulate the flow of antibiotics in and out of the cell. Antibiotic resistant, gram negative bacteria may have genes that reduce porin channels available for drug uptake or increase the number of available efflux pumps (in the OM) for antibiotics, whereas gram positive bacteria might only be able to modifying the shape of the target molecule to inhibit antibiotic binding (2). Thus, finding strategies to fight Gram-negative bacteria has been a great challenge for scientists.

Scientists have used methods like utilizing antimicrobial auxiliary agents or modifying structures of existing antibiotics to fight and control resistant Gram-negative bacteria (4). However, a recent study done by Princeton researchers could shift the direction of antibiotic research in the future. The group of researchers led by Dr. James K. Martin has found a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action: it can simultaneously puncture bacterial walls and destroy folate within their cells, thus being immune to antibiotic resistance (6). The group calls this mechanism “poisoned arrow,” as the arrow targets the outer membrane -- piercing through even the thick armor of Gram-negative bacteria -- while the poison shreds folate, a fundamental building block of RNA and DNA (7). 

It may be noted that no new classes of Gram-negative-killing drugs have come to market in nearly 30 years. Thus, the discovery of this compound and its derivatives--called Irresistin, since they are irresistible--may be seen as a new hope in antibiotic development. Not only is Irresistin effective against both Gram-negative and Gram-positive bacteria, but it can also be safely tolerated in animals and humans, and it will endure a much longer time than current antibiotic drugs due to its undetectable resistance. 

This poisoned arrow paradigm could revolutionize antibiotic development, said KC Huang, a professor at Stanford University who was not involved in this research. "A study like this says that we can go back and revisit what we thought were the limitations on our development of new antibiotics. From a societal point of view, it's fantastic to have new hope for the future (7)."



References: 

  1. Biomedical Open Access Journal For Medical and Clinical Research. (n.d.). Retrieved July 02, 2020, from https://biomedres.us/fulltexts/BJSTR.MS.ID.000117.php
  2. Kapoor, G., Saigal, S., & Elongavan, A. (2017). Action and resistance mechanisms of antibiotics: A guide for clinicians. Retrieved July 02, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672523/
  3. Hannah Jordt, Thibault Stalder, Olivia Kosterlitz, José M. Ponciano, Eva M. Top, Benjamin Kerr. Coevolution of host–plasmid pairs facilitates the emergence of novel multidrug resistance. Nature Ecology & Evolution, 2020; DOI: 10.1038/s41559-020-1170-1
  4. Breijyeh, Z., Jubeh, B., & Karaman, R. (2020, March 16). Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It. Retrieved July 02, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144564/
  5. Hauser AR, editor. Cell envelope. Antibiotic Basic for Clinicians. 2nd ed. New Delhi: Wolters Kluwer (India) Pvt. Ltd; 2015. pp. 3–5. [Google Scholar]
  6. James K. Martin, Joseph P. Sheehan, Benjamin P. Bratton, Gabriel M. Moore, André Mateus, Sophia Hsin-Jung Li, Hahn Kim, Joshua D. Rabinowitz, Athanasios Typas, Mikhail M. Savitski, Maxwell Z. Wilson, Zemer Gitai. A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance. Cell, 2020; DOI: 10.1016/j.cell.2020.05.005
  7. 'Poisoned arrow' defeats antibiotic-resistant bacteria. (2020, June 03). Retrieved July 02, 2020, from https://www.sciencedaily.com/releases/2020/06/200603132541.htm
  8. Wilson, D. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol 12, 35–48 (2014). https://doi.org/10.1038/nrmicro3155