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F. tularensis, tularemia, antibiotic-resistant bacteria, antibiotic resistance, bacterial biothreats, Live Vaccine Strain biofilm

Live Vaccine Strain biofilm
Live Vaccine Strain biofilm screening in 96-well plates, (USAMRIID photo by William Discher)

Biothreats persist in their pursuit; developing new antibiotics is a way to stay ahead. Researchers are developing new antibiotics to combat common bacteria that are becoming increasingly resistant to antibiotic treatment, which is a growing concern for both public health and Joint Force readiness. Both emerging pathogens and known biothreats, such as Bacillus anthracis (anthrax), pestis (plague), Francisella (F.) tularensis (tularemia, also called "rabbit fever"), Burkholderia mallei (glanders), and Burkholderia pseudomallei (melioidosis), are all capable of antibiotic resistance–whether naturally occurring or deliberately engineered by an adversary.

To help deter the threat of antibiotic resistance in these pathogens, the Defense Threat Reduction Agency's (DTRA) Chemical and Biological Technologies Department in its role as the Joint Science and Technology Office (JSTO) for Chemical and Biological Defense, an integral component of the Chemical and Biological Defense Program, partnered with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and Walter Reed Army Institute of Research to identify targets for developing new antibiotics.

Recently, USAMRIID investigators collaborated in screening chemical compounds for potential use against F. tularensis, the cause of tularemia in humans. Tularemia is typically carried by rodents and rabbits in the Northern Hemisphere and can spread to humans through contact with infected animal tissues, deer flies, and ticks. While the overall number of human tularemia cases is small (about 300 per year in the United States), the bacterium is designated by the Department of Health and Human Services and the U.S. Department of Agriculture as a Tier 1 select agent, "presenting the greatest risk of deliberate misuse with most significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence," because of its low infectious dose (as few as 10–15 organisms), high morbidity, and ease of aerosolized inoculation, which make it a potential biological weapon.

Current antibiotics such as fluoroquinolones (Cipro and Avelox) and aminoglycosides (Gentamicin and Streptomycin) are effective for treating tularemia; however, high levels of resistance have been increasingly observed for this and other gram-negative pathogens, and there is a well-documented ability to derive resistant Francisella strains. Given these conditions, there is a need to identify new therapeutics to combat tularemia in the event resistant F. tularensis isolates or variants threaten the Joint Force.

USAMRIID's team implemented a two-pronged approach for identifying antibacterial compounds to combat antibiotic resistance in F. tularensis (and potentially other bacterial biothreats and public health pathogens).

The first approach is to examine targets of F. tularensis that are critical to the bacteria and then exploit these targets to identify new inhibitors. Current laboratory efforts focus on three structures of the bacterium: biofilm, peptidoglycan, and lipopolysaccharide.

The second approach is to cast a broader net to identify new inhibitors. USAMRIID has a procedure for high-throughput screening of compounds able to block the growth of Live Vaccine Strain–a version of F. tularensis that can be safely handled in a Biosafety Level 2 laboratory. So far, the team has screened nearly 50,000 compounds from an exploratory chemical library.

Several compounds are currently being characterized to determine if inhibition occurs with the fully virulent bacteria (in a Biosafety Level 3 laboratory) to ensure that surrogate screening can be recapitulated in relevant strains. Other studies are underway to assess the suitability of these compounds for further development as antibiotics, and to determine whether they could be used against additional bacterial threat agents.

The next step for this drug discovery process is to test the lead compounds from the library for their ability to protect against F. tularensis in a challenge model. The successful lead candidates will be considered for advanced development and future clinical trials so that DTRA JSTO can prevail against F. tularensis and other similar and future biological threats.

POC: MAJ Tiffany Nguyen;

Last Modified Date: 9-Jan-2024