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Latest News from the NCDIR

1608, 2020

Research Spotlight – NCDIR scientists propose new strategies for developing antiviral therapeutics to target SARS-CoV-2 and other viruses.

August 16th, 2020|

In a new Perspective published in the Journal of Cell Biology, scientists from the NCDIR propose several new strategies for developing antiviral therapeutics to target SARS-CoV-2 and other viruses. Drawing inspiration from a well-established molecular phenomenon whereby certain combinations of genetic alleles produce strong negative effects on cell viability, termed synthetic lethality, they propose several strategies for developing therapeutics that are specifically designed to induce synthetic lethality in virus-infected cells.

Analogous to how the legs of a table function to keep the table sturdy and capable of reliably holding objects on its surface, cells also have redundant systems that help maintain cell health. When viruses infect cells, they exploit this redundancy by hijacking host machinery to produce new virions. But like the precarious state of a wobbly table missing one leg, viruses weaken and remove redundancy in cells and induce specific vulnerabilities that could be exploited by therapeutic intervention. Such an approach has several advantages over traditional antiviral strategies as it would ensure specificity for viral-infected cells while simultaneously minimizing off-target effects and the emergence of drug resistance. Similar approaches have had success in the development of therapeutics for certain types of cancer, but until now, the concept has not been extended to infectious disease. You can read more about this exciting development here.

Figure 1. We use the analogy of a table being supported by four legs to illustrate the concept of synthetic lethality and its application to druggable targets. (A) Like the legs of a table, cells have redundant features that make them robust to perturbation. (B) When two legs of a table are removed, the table no longer can remain stable and collapses after removal of the second leg. Similarly, synthetic lethality in a cell occurs when two essential components of a redundant system are removed, causing cell death. (C) The principle of synthetic lethality has been used to develop drugs that target a redundant system of the cancer-causing genetic mutations. (D) Synthetic targeting of viruses is a variant of synthetic lethality, where drugs are designed to target systems redundant with host proteins co-opted to produce new virions and thus, cripple the host cell virus factory.

1305, 2020

Research Spotlight – NCDIR scientists have developed ODELAM, a technique to study drug resistance in Mycobacterium tuberculosis

May 13th, 2020|

NCDIR scientists led by Dr. Thurston Herricks in the lab of Prof. John Aitchison (Seattle Children’s) developed a novel time-lapse microcopy approach for high throughput analysis of Mycobacterium tuberculosis growth to understand its genetic-environment interactions.  One very important application of this work is investigating how pathogens like Mycobacterium tuberculosis (Mtb) respond to antibiotics and develop resistance. 

Growth of Mtb strain H37Rv into microcolonies over time observed with ODELAM Selected time-lapse snapshots of Mtb colonies growing on a solid medium. Mtb CFUs are shown growing on a 60 μm x 60 μm region of 7H9-GO agar over 96 hrs time course. (B) Growth curves for a total of 1276 colonies were recorded from a 1.2 mm x 0.9 mm region over 96 hrs and plotted. (C) Population histograms of the all extracted growth parameters (Doubling Time, Lag Time, Exponential Time and Number of doublings).

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.  We anticipate these investigations will provide additional information for the design of new antibiotics and inform more effective application of antibiotics to patients.

1402, 2020

RockEDU profiles NCDIR scientist Dr. Natalia Ketaren!

February 14th, 2020|

RockEDU Science Outreach at The Rockefeller University has featured NCDIR scientist Dr. Natalia Ketaren as their February #SCIONY (Scientists of New York)!

Read Natalia’s interview for RockEDU in the link below!

 

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