Kalyssa Platt | October 6th, 2024
Antibiotic resistance is one of the world’s most urgent health problems, as it can affect individuals at any stage of their life and killed over 1.27 million people worldwide in 2019. It occurs when bacteria and fungi develop resistance mechanisms by acquiring external genetic material against antibiotics, decreasing the effectiveness of the medication.
There are three main ways bacteria may gain antimicrobial resistance: transformation, transduction, and conjugation. In transformation, the most simple type, naked DNA is incorporated into the bacteria to give resistance. Transduction is a type of horizontal gene transfer where a bacteriophage is used as an intermediate.
Conjugation is the most popular in the hospital environment. It involves cell-to-cell contact and is very widespread in the human gastrointestinal tract. Conjugation works by using mobile genetic elements, like plasmids and transposons, to share their genetic information. Plasmids are small, circular DNA molecules, separate from chromosomal DNA, that carry genetic information that may be helpful to bacteria for antibiotic resistance. In conjugation, the plasmid of one bacterium can be transferred to another through physical contact, causing the receiving bacterium to integrate the genetic material of the plasmid and eventually expressing the gene of antibiotic resistance. Similarly, transposons are sections of DNA that can “jump” from one location in a genome to another, which, if located on a plasmid during conjugation, can be transferred to another bacterium and cause the new bacterium to obtain the gene that allows for antibiotic resistance.
Combating antibiotic resistance
There are some helpful strategies for individuals and healthcare providers to more simply prevent antibiotic resistance. By using antibiotics correctly and taking them only when necessary, the chances of obtaining antimicrobial resistance decrease significantly. Individuals should not take an antibiotic for a virus, take the medication exactly as prescribed by finishing the entire prescribed dosage regime, and never take an antibiotic prescribed for another individual. Healthcare professionals should only prescribe needed antibiotics, prescribe medicines for the full course, and target the medicine to the specific bacteria.
Vanderbilt’s Merrikh Lab
Vanderbilt biochemist Houra Merrikh recently led her team to the discovery of the first evolution-resistant chemical compound that would prevent antibiotic resistance. The team had previously determined that a protein responsible for moving molecules from one cell membrane to another, DNA translocase Mfd, is what speeds up the presentation of antimicrobial resistance (AMR).
The lab’s strategy has been to directly target and inhibit bacterial mechanisms that increase mutation rates, lowering the number of mutations that may lead to resistance. In particular, this method involves inhibiting the activity of DNA translocase Mfd.
The team has discovered a small molecular compound, ARM-1, that is able to moderate the activity of Mfd and can reduce both target-specific and non-target-specific mutagenesis. This compound binds tightly to the Mutation Frequency Decline protein (Mdf). ARM-1 treatments led to reductions in mutagenesis and mutation rates in various bacteria and inhibited the development of antibiotic resistance within many pathogens and antibiotics, including multidrug-resistant strains. Furthermore, bacteria do not develop resistance against the ARM-1 compound even after multiple exposures, demonstrating its effectiveness.
Future implications
This research has significant implications for the fight against antimicrobial resistance, including the recognition of Mfd as the target of the problem, identification of AMR-1, and the necessary mode of action. Since ARM-1 treatments exhibited a successful inhibition of the evolution of antibiotic resistance, there are potential clinical applications. ARM-1 could be developed into a drug to prevent the development of antimicrobial resistance throughout infection treatments. The discovery of this compound also demonstrates that it is possible to inhibit the evolution of antibiotic resistance with just a small molecule. Further research on similar compounds could lead to discoveries of more antimicrobial agents with even greater effectiveness and possible applications.
References
“About Antibiotic Resistance.” Centers for Disease Control and Prevention, Centers for Disease
Control and Prevention, 5 Oct. 2022, www.cdc.gov/drugresistance/about.html.
“Antibiotic Resistance.” Edited by Diane Horowitz et al., Cedars, The StayWell Company, LLC,
www.cedars-sinai.org/health-library/diseases-and-conditions/a/antibiotic-resistance.html
Carvajal-Garcia, Juan, et al. “A Small Molecule That Inhibits the Evolution of Antibiotic
Resistance.” Oxford Academic, Oxford University Press, 23 Jan. 2024,
academic.oup.com/narmolmed/article/1/1/ugae001/7585174#google_vignette.
Munita, Jose M, and Cesar A Arias. “Mechanisms of Antibiotic Resistance.” PubMed Central,
U.S. National Library of Medicine, Apr. 2016,