For many of us, when we fall ill with a cough, flu, or sore throat, our first instinct is to visit a doctor to seek relief of our symptoms. A few hours later, we leave the clinic armed with antibiotics that will seemingly treat everything from sinus infections to strep throat. However, as miraculous as these drugs may seem, bacterial resistance to these antibiotics has arguably become the largest public health challenge of this generation (Centres for Disease Control and Prevention, 2018). It is estimated that each year in the United States alone, around two million people will develop an infection that is resistant to antibiotics, and over 23,000 patients will die as a result (Centres for Disease Control and Prevention, 2018). Clearly, antibiotic resistance is increasingly becoming a medical problem, and researchers are attempting to find a solution to this crisis. The answer could lie in a new discovery by researchers at Case Western Reserve University, who have shown that antivirulence agents have potential to be used as a replacement for antibiotics, or to be used adjunctively in the course of treatment (Greenberg et al., 2018a).
These antivirulence agents differ from antibiotics because instead of killing the bacteria that cause an infection, they prevent the pathogen from being effective in the body (Greenberg et al., 2018a). This is done by targeting the part of the molecule that produces the toxins within the bacteria, blocking its virulence (Heras, Scanlon, and Martin, 2015). Since the bacteria is not killed, resistant strains are not highly selected for (Greenberg et al., 2018a). This method decreases survival advantage for the more lethal strains, making it more effective at combatting antibiotic resistance (Greenberg et al., 2018a).
In their models, scientists from Case Western Reserve used the antivirulence agents F12 and F19, as shown in Figure 1, which target the toxin-producing agr system of Staphylococcus aureus (Greenberg et al., 2018a). These agents block AgrA, which is a transcription factor, from binding to the promoter; this prevents transcription, inhibiting the expression of the toxin that harms the body (Greenberg et al., 2018a). Many other gram positive bacteria have analogous factors to AgrA, which led them to believe these antivirulents would also be effective on other organisms in addition to S. aureus (Greenberg et al., 2018a).
Researchers carried out in vivo trials that involved infecting mice with MRSA, (Greenberg et al., 2018a) a bacteria which is highly resistant to antibiotics (Pantosti and Venditti, 2009) The animals were separated into a variety of treatment groups; after one week, all mice treated with F19 or a combination of F19 and antibiotics were living and healthy (Greenberg et al., 2018a). One of the mice in the antibiotic only group had perished, and the remaining living animals in that group had a lower health score than those treated with F19 (Greenberg et al., 2018a).
These results can also be extended to other strains of bacteria; since all gram-positive bacteria have agr operons, antivirulence agents can treat a variety of infections, including those caused by Staphylococcus, Streptococcus, and Bacillus (Greenberg et al., 2018a). Researchers hypothesize that in healthy individuals, F19 could potentially be used to cure bacterial infections, but recommend that for patients with weakened immune systems, a combination therapy is likely a better course of treatment (Greenberg et al., 2018a).
It is believed that by 2050 more people will be dying each year from antibiotic resistance than from cancer if this global health issue is not addressed (Totsika, 2016). Although researchers at Case Western Reserve University have made a promising discovery, the battle against antimicrobial resistance is far from over, and more research is required if we are to combat this public health crisis.
Works Cited:
Centres for Disease Control and Prevention, 2018. Antibiotic Resistance Threatens Everyone. [online] Centers for Disease Control and Prevention. Available at: <https://www.cdc.gov/drugresistance/index.html> [Accessed 24 Feb. 2019].
Greenberg, M., Kuo, D., Jankowsky, E., Long, L., Hager, C., Bandi, K., Ma, D., Manoharan, D., Shoham, Y., Harte, W., Ghannoum, M.A. and Shoham, M., 2018a. Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens. Scientific Reports, 8(1), p.14578.
Greenberg, M., Kuo, D., Jankowsky, E., Long, L., Hager, C., Bandi, K., Ma, D., Manoharan, D., Shoham, Y., Harte, W., Ghannoum, M.A. and Shoham, M., 2018b. Structural formulae of F12 and F19. Available at https://www.nature.com/articles/s41598-018-32829-w/figures/2 [Accessed 24 Feb. 2019].
Heras, B., Scanlon, M.J. and Martin, J.L., 2015. Targeting virulence not viability in the search for future antibacterials. British Journal of Clinical Pharmacology, 79(2), pp.208–215.
Pantosti, A. and Venditti, M., 2009. What is MRSA? European Respiratory Journal, 34(5), pp.1190–1196.
Totsika, M., 2016. Benefits and Challenges of Antivirulence Antimicrobials at the Dawn of the Post-Antibiotic Era. Current Medicinal Chemistry, 6(1), pp.30–37.