Contact Cindy Foster (505) 269-6035 for more inforamtion
In recent years, the possibility of biological warfare and bioterrorism has become of increasing concern to both military planners and civil defense authorities. Researchers at the UNM Health Sciences Center are leading part of a team investigating possible countermeasures that can be used against two pathogens found in nature that have the potential to be used in biological warfare.
Funded by an $8.4 million contract from the U.S. Defense Threat Reduction Agency, it is anticipated the research will also be able to impact public health threats.
Tularemia, caused by Francisella tularensis, is one of the most infectious pathogenic bacteria known—inhalation of as few as 10 organisms can cause disease—and it has substantial capacity to cause serious illness and death. Melioidosis, caused by Burkholderia pseudomallei, is an equipotent biological threat with public health importance in endemic areas, particularly Thailand and northern Australia with increasing frequency in other parts of the world.
There is a high military and medical need to devise strategies leading to implementation of effective countermeasures for both biological warfare agents (BWAs). Efflux mechanisms are broadly recognized as major components of multidrug resistance to many classes of antimicrobials.
Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES) or pumps. These pumps are responsible for expelling antibiotics from microbial cells. They are implicated in physiological roles other than efflux; thus, identifying substrates and efflux pump inhibitors (EPIs) is an active and expanding discipline. The challenge of reversing the activity of efflux pumps has been viewed as an attractive approach in the deployment of effective antibiotics.
“We have proposed an antimicrobial discovery platform targeting the efflux systems of F. tularensis and B. pseudomallei,” said George Tegos, Ph.D., Department of Pathology and center for Molecular Discovery. “This approach incorporates target validation, assay development and HTS flow cytometry campaigns with enhancements based on substrate multiplexing. Repurposed approved drugs, libraries of substrates and inhibitors of efflux, as well as combinatorial libraries will undergo evaluation and detailed biological characterization (efficacy to potentiate antibiotics, resistance studies and toxicity in red blood cells and non-vertebrate hosts) as well as in vivo validation in selected animal models.”
This initiative will provide lead EPIs targeting MES for these pathogens for preclinical implementation and toxicity as well as in vivo validation in selected animal models.
The scientific team consists of Prof. George Tegos and Prof. Larry Sklar (University of New Mexico Center for Molecular Discovery, UNMCMD), Prof Tudor Oprea and Prof Christian Bologa (Division of Translational Informatics and UNMCMD), Prof. Terry Wu and Prof Julie Lovchick (UNM - Center for Infectious Disease and Immunity, UNM-CIDI), Drs. R. Houghten and C. Pinilla (Torrey Pines Institute for Molecular Studies, TPIMS), Prof. Herbert P. Schweizer (IDRC at Foothills Campus - Colorado State University, CSU) and Prof. Eleftherios Mylonakis (Alpert Medical School, Brown University).
Efflux HTS assays will be performed (Tegos and Sklar) employing a focused set of chemical libraries, as well as one novel collection of efflux inhibitors; lead chemotypes will be identified (Houghten, Pinilla and UNMCMD Screening Informatics, Oprea and Bologa); compounds will be validated in vitro for their ability to enhance antibiotic responses (Wu and Schweizer) and will be prioritized through non-vertebrate host in vivo activity and toxicity studies (Mylonakis) for pharmacokinetics/pharmacodynamics (PPL Inc.).
Contact: Cindy Foster, 272-3322