Publication Q&A: ODELAM Rapid Sequence-Independent Detection of Drug Resistance in Isolates of Mycobacterium Tuberculosis
June 2020 – Thurston Herricks shares insights from a recent publication in eLife with contributing authors from the Aitchison Lab at the Center for Global Infectious Disease Research (CGIDR).
ODELAM Rapid Sequence-Independent Detection of Drug Resistance in Isolates of Mycobacterium Tuberculosis
Thurston Herricks, Magdalena Donczew, Fred D. Mast, Tige Rustad, Robert Morrison, Timothy R. Sterling, David R. Sherman, John D. Aitchison
Published in eLife, May 2020
What is your lab’s current research focus?
The Aitchison Lab’s research involves using systems cell biology to investigate host-pathogen interactions. The goal of systems cell biology is to understand how proteins, genes and molecules come together and interact as a system to form a functioning and living organism. For relatively simple single-cell organisms like yeast or bacteria, the ensemble of these genetic and environmental interactions can be measured by watching the individual cells grow under a microscope. One very important application of this work is investigating how pathogens like Mycobacterium tuberculosis (Mtb) respond to antibiotics, as this helps inform how Mtb develops antimicrobial resistance or drug resistance.
What is the significance of the findings of this publication?
Antibiotics are required to treat a wide variety of microbial infections. However, with continued use of antibiotics, pathogens have developed antibiotic resistance that has rendered some antibiotics ineffective. Mtb, the microbe that causes tuberculosis, is particularly deadly, killing approximately 1.1 million people per year. Like other bacteria, Mtb has evolved mechanisms to resist the effects antibiotics. Understanding how antibiotic resistance emerges is critical for the development of countermeasures to battle emerging antibiotic resistance. We developed a technique named One-Cell Doubling Evaluation of Living Arrays of Mycobacterium, or ODELAM, that uses a microscope to automatically watch tens of thousands of individual Mtb cells grow over time as they are exposed to antibiotics. Remarkably, although cells are genetically identical, individual cells in a population respond differently to antibiotic drugs. This so-called antibiotic-induced population heterogeneity is key to how organisms like Mtb develop antibiotic resistance. The detailed growth measurements that ODELAM provides offer insight into the mechanisms of how antibiotics kill Mtb and what strategies Mtb develops to become resistant to antibiotics. The sensitivity of ODELAM allows us to detect different resistance states in individual clinical isolates. This is critical for detecting very small populations of resistance that can persist despite drug treatment.
What are the next steps for this research?
The Aitchison Lab is continuing to develop new techniques and technologies that are critical for investigating how pathogens interact with antibiotics but also more generally, how genetic and environmental interactions play out as a system in an organism’s behavior. Following development of ODELAM and previously ODELAY, we are integrating these technologies into investigating mechanisms of cellular responses to antibiotics. With ODELAM we are continuing to explore how front-line antibiotics affect growth and heterogeneity of Mtb as well as Mycobacterium abscessus. We anticipate these investigations will provide additional information for the design of new antibiotics and inform more effective application of antibiotics to patients.
Seattle Children’s CGIDR contributing authors: