Bacteria have been divided into two large, broad groups: gram-negative and gram-positive. The major difference between these two types is structure of their cell walls, or the outside membranes of bacteria that give them their rigidity and shape. Gram-positive bacteria only have an inner membrane surrounded by a thick layer of sugar and amino acids, known as peptidoglycan. The cell wall of gram-negative bacteria has an outer and inner membrane, with a thin layer of peptidoglycan in between. The outer membrane in gram-negative bacteria prevents more drugs and antibiotics from infiltrating and killing the bacterial cell, which makes gram-negative bacteria generally more resistant to antibiotics (1). This difference in cell wall structure makes it so that while gram-positive bacteria can be treated with a certain antibiotic, that same antibiotic may not be able to treat gram-negative bacteria.
Additionally, more bacteria are becoming resistant to antibiotics, making treatment difficult (2). With limits on antibiotics that can be used for treatment in the first place along with bacteria growing more resistant to antibiotics, the need for new drugs in treating bacterial infections has spawned a new approach to antibiotics: the Trojan horse method.
In order to survive in their different environments, bacteria have developed special processes to meet their needs. For example, bacteria need iron ions to live. Since they cannot always synthesize or find it, they secrete iron-harvesting molecules that search the environment for iron ions (3). Once the iron-harvesting molecule has attached to an iron ion, the molecule moves back into the bacterial cell through protein channels.
Scientists utilized this mechanism to create a deadly antibiotic duo disguised as an iron-harvesting molecule. The proposed drug is a syderomycin, a synthetic iron-harvesting molecule with two antibiotics attached to it (3). The syderomycin has an antibiotic commonly used to treat gram-negative bacteria followed by an antibiotic used to treat gram-positive bacteria. This drug is aimed at treating gram-negative bacteria by getting past the membranes of the bacteria that would otherwise render the antibiotics ineffective.
The iron-harvesting molecule of the syderomycin would deceive the gram-negative bacteria into believing that it is delivering iron, though it is instead delivering antibiotics. This allows the drug to pass through the outer membrane of the bacteria. Some bacteria have developed mechanisms to defend against intruders, one of the mechanisms being the destruction of the antibiotic. The bacterium would then release an enzyme that kills the first antibiotic, but the death of the antibiotic would trigger the release of the second antibiotic. This next antibiotic would cause the the bacterium to undergo suicide.
The researchers used a syderomycin containing the antibiotics cephalosporin and oxazolidinone on the gram-negative bacteria Acinetobacter (4). This bacteria releases an enzyme capable of killing cephalosporin, which would then spawn the second antibiotic oxazolidinone. Originally, oxazolidinone is not used to treat gram-negative bacterial infections as it cannot get past the membranes of the bacterial cell. Now that it can sneak in, the structure and defense mechanisms of the bacteria are no longer barriers to treatment.
While bacteria may evolve to have some tricks up its sleeves, new technology has even more tricks up its sleeves. When thinking of the Greeks and the Trojan horse, do not forget that antibiotics have their own Trojan horse as well–except it’s an iron-harvesting molecule instead.
(1) Kaplan, Melissa. The Problem with Gram-Negative Bacteria. 2000, www.anapsid.org/gramnegative.html.
(2) Schalk, Isabelle J. “A Trojan-Horse Strategy Including a Bacterial Suicide Action for the Efficient Use of a Specific Gram-Positive Antibiotic on Gram-Negative Bacteria.” Journal of Medicinal Chemistry, vol. 61, no. 9, 2018, pp. 3842–3844., doi:10.1021/acs.jmedchem.8b00522.
(3) Berezow, Alex. ‘Double Trojan Horse’ Drug Tricks Bacteria into Committing Suicide. American Council on Science and Health, 12 May 2018, www.acsh.org/news/2018/05/12/double-trojan-horse-drug-tricks-bacteria-committing-suicide-12954.
(4) Liu, Rui, et al. “A Synthetic Dual Drug Sideromycin Induces Gram-Negative Bacteria To Commit Suicide with a Gram-Positive Antibiotic.” Journal of Medicinal Chemistry, vol. 61, no. 9, 2018, pp. 3845–3854., doi:10.1021/acs.jmedchem.8b00218.