Laboratory for Combinatorial Drug Regimen Design for Resistant and Emerging Pathogens

(a) Overview The past two years have shown that infectious diseases are global threats, revealing an urgent need to improve preparedness to combat unknown pathogens. Furthermore, the alarming increase in infections caused by antimicrobial resistant (AMR; see glossary, below) pathogens in recent years, exacerbated by the COVID-19 pandemic, illustrates that we are also on the verge of losing our ability to treat infections caused by known pathogens. Combination drug treatment is the therapeutic mainstay in the treatment of infections caused by several microbial pathogens, including HIV and the tuberculosis bacterium. Still, systematic and efficient development of such treatments for AMR or emerging pathogens is lacking. Tufts University (TU) is proposing to construct a new biomedical research facility, the Laboratory for Combinatorial Drug Regimen Design for Resistant and Emerging Pathogens (LCDRD), to design and develop new combinatorial therapeutic approaches for bacterial, viral, fungal, and parasitic infections and to accelerate research on AMR and emerging pandemic pathogens. The LCDRD is designed to facilitate the development of novel treatments for difficult-to-treat infections due to pathogens from both animals and humans. In addition to generating new therapies for AMR or emerging pathogens, this facility will provide diverse, well-characterized human bacterial pathogens with linked clinical data from across 'Tufts-Medicine', a state-wide network of hospitals serving diverse populations, for study by academia and industry. The Stuart B. Levy Tufts Center for Integrative Management of Antimicrobial Resistance (CIMAR) unites faculty from TU and Tufts Medical Center (TMC), as well as affiliate members from across the region and nation, with expertise in biomedical research, engineering, human and veterinary medicine, global health, environmental surveillance, policy, and education, to catalyze the development of new combinatorial drug strategies to treat a wide range of pathogens. Working with CIMAR in LCDRD will be the nascent Center for Emerging Infectious Diseases and Response (CEIDAR), which addresses emerging and expanding infectious disease threats such as insect-borne bacterial and viral pathogens. CEIDAR includes the Tufts Lyme Initiative and utilizes the BSL-3 level Tufts New England Regional Biosafety Laboratory (NERBL) at Tufts Cummings School of Veterinary Medicine in Grafton, an important resource for expanding work. Institutions affiliated with CIMAR/CEIDAR span a spectrum of academic and pharmaceutical interests and, although located locally at TU, will enhance transdisciplinary interactions among regional and national investigators and entities. Project Goals: The LCDRD will enable specialized and collaborative work on emerging and resistant microbial pathogens that is required to generate new combinatorial treatments. The facility will: 1) enhance interaction between clinicians and biomedical researchers to generate therapeutic antimicrobial drug regimens, particularly combination therapies, against CDCs urgent and emerging threat pathogens; 2) develop genetic and systems approaches to facilitate 'personalized medicine' for patients with difficult-to-treat infection; 3) provide a space where visiting scientists can receive hands-on training, allowing knowledge dissemination intra-institutionally, regionally, nationally, and globally; and 4) increase the national capacity to respond to infectious disease emergencies by providing academic and industrial entities access to libraries of well-characterized isolates for emerging pandemic and AMR pathogens. Affected Space and Requested Equipment: The LCDRD will provide a modern, centralized laboratory and collaboration capacity for a multi-institutional effort to utilize state-of-the-art research technologies to generate and characterize novel drug therapies for pathogens resistant to current therapeutic regimens as well as new pandemic threats. It will provide a specialized and biosecure environment for researchers to work with multi- drug resistant (MDR) and emerging pathogens. It will be built in an existing 2,400 sq. ft. shell space in the Biomedical Research and Public Health Building on the Tufts Health Sciences campus in Boston. The new facility, directly adjacent to Tufts' existing BSL-3 lab and the laboratories of the PI and a key CIMAR investigator, will be shared by teams of interdisciplinary researchers from four TU schools and TMC, as well as collaborators from other regional and national institutions. Impact on Research and Clinical Practice: The National Health Security Strategy, 2019-2022, states that "the growing incidence of AMR has both public health and national security consequences" and that "expanding the antimicrobial arsenal is a real and immediate requirement to avoid an era of untreatable infectious diseases." Through centralizing and leveraging our expertise in bacterial, viral, and MDR pathogens, innovative measures of combinatorial drug efficacy, and deep clinical expertise in treatment-resistant infections, the LCDRD will support the nation's AMR crisis response by generating novel therapies, both at Tufts and in collaboration with other academic and pharmaceutical entities across the country (Fig. 1). LCDRD will be a national center of excellence that makes broadly available well-characterized pathogens with clinical data, allowing for linkage of patient outcomes to strain-level pathogenicity and combination therapy. This will enable a true link from bedside to bench and back-a feedback loop that will maintain a tight translational focus, inform treatment regimens for current and emerging threats, and promote personalized medicine.