Kathleen Davis, PhD, Postdoctoral Scholar Working on Adapting Drug Combination Testing of Clinical Isolates
Fall 2021 Featured Trainee:
Kathleen Davis, PhD
- Postdoctoral Scholar in the Bree Aldridge Lab, working with Drs. Aldridge and TMC’s Roberto Viau Colindres on adapting drug combination testing of clinical isolates
- Working to identify antibiotic and small molecule combinations that function against problematic community and hospital-acquired pathogens in a multi-institution collaboration through the Center for Innovation to Transform Antibiotic Discovery (CITADel)
Kathleen Davis is a second-year postdoctoral scholar in the Bree Aldridge Lab at Tufts University’s School of Medicine. She is working to develop a method of in-vitro testing of drug regimens on bacterial pathogen clinical isolates from Tufts Medical Center patients with severe infections. The goal of this collaborative project, which is funded by a Levy CIMAR pilot grant awarded to the Aldridge Lab and the Levy CIMAR’s Roberto Viau Colindres, MD, of the medical center, is to design in-vitro testing methodology to help choose more effective regimens for serious infections. In addition, Kathleen is working in collaboration with other university labs and biotech companies, through the multi-institution Center for Innovation to Transform Antibiotic Discovery (CITADel), on identifying small molecules that can be used in combination with antibiotics to restore or improve the activity of those antibiotics against community and hospital-acquired bacterial infections.
Identification of treatment regimens for bacterial infections is often based in part on an antibiogram, which indicates whether a pathogen cultured on standard laboratory growth medium is sensitive, resistant or intermediate resistant to a particular antibiotic. Treatment with that antibiotic is not always effective, and often multiple antibiotics are needed to treat serious bacterial infections, which cannot be effectively tested in combination using an antibiogram. Kathleen is exploring the use of diagonal measurement of n-way drug interactions (DiaMOND) to speedily test regimens on clinical isolates. DiaMOND is a methodology developed by the Aldridge Lab to measure the information-rich diagonal of a standard checkerboard assay, allowing higher-throughput measurement of drug combinations. Prior to DiaMOND, scientists’ understanding of high-order drug interactions was limited because of the lack of both efficient measurement methods and theoretical framework for analysis and interpretation. (You can learn more about DiaMOND here).
Increasing drug resistance against many antibiotics is a major problem for treating serious bacterial infections, particularly those that are hospital-acquired. As part of a project through CITADel, Kathleen is working to identify small molecules which restore or improve the activity of antibiotics against problematic bacterial pathogens including Acinetobacter baumannii and Pseudomonas aeruginosa. Kathleen is using DiaMOND to efficiently measure how well antibiotic plus small molecule pairs function against a variety of clinical isolates in multiple growth conditions to mimic the range of stressors experienced by the bacteria during real-life infection. The team is working to bring some combinations to early clinical trials.
Prior to joining the Aldridge Lab, Kathleen earned her PhD in the Dr. Alan Grossman Lab at MIT’s Department of Biology. There, she studied exclusion, a method by which some genetic elements prevent their host bacterial cells from receiving a second identical copy of the element from a would-be donor bacterial cell. Exclusion often involves a protein encoded by the genetic element that recognizes and inhibits the transfer machinery encoded by the identical element in the would-be donor cell. This transfer machinery (known as a conjugation system) can also move other genetic material into a would-be recipient cell, including antibiotic resistance genes. Thus, exclusion plays an important role in controlling the spread of antibiotic resistance among bacterial populations via a type of horizontal gene transfer known as conjugation. Kathleen studied exclusion in the genetic element ICEBs1 in Bacillus subtilis, and identified the target protein ConG recognized by the exclusion protein YddJ. Kathleen also identified portions of both proteins key for specific recognition, which allows YddJ to only exclude conjugation machinery encoded by ICEBs1 and not closely related elements.
When not working in the lab, Kathleen loves to get outside. She spends much of her free time exploring mountains, canyons, rocky coastlines, and tide pools. She also enjoys hiking, backpacking, biking, and kayaking.