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Many thanks to many members of the Yang Lab who contributed to this project (including many undergrads!) and to our collaborators Douglas McCloskey and Xiaoyang Su! 11/11 @njms-mdphd.bsky.social

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We're eager to explore these topics in future projects and to see how generalizable these phenotypes are to pathogenic E coli and other species. We think these mechanisms may inform design of antibiotic adjuvants that can slow or prevent resistance development. 10/n

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Importantly, little is known on how energy balance alters bacterial physiology. Although metabolic stress is known to inhibit growth and enhance metabolism, our work is the first to study stress responses and antibiotic phenotypes caused by disrupted energy balance. 9/n

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By developing a new assay, Barry showed that mismatches between ATP utilization and production (disrupting ATP homeostasis) are sufficient for augmenting antibiotic killing. Thus, Barry's work introduces new concepts in understanding the interplay between energy balance and antibiotic efficacy. 8/n

Using bacterial genetics approaches, Barry was able to show that bioenergetic stress mechanistically induces stress responses that increase antibiotic stress-induced mutation rates and that protect against antibiotic killing. 7/n

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This was also surprising that we previously showed that high levels of reactive oxygen species (ROS) were associated with high antibiotic killing, but the pF1 and pNOX cells had decreased killing while also possessing high levels of ROS! 6/n

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Correlations between ATP availability and persistence are known and are usually thought about as correlations between metabolic activity (e.g., dormancy, low ATP) and killing efficacy. But Barry's cells have HIGH metabolic activity, which we previously found to INCREASE antibiotic killing. 5/n

Surprisingly, Barry found that bioenergetically stressed cells evolve antibiotic resistance FASTER than control cells (!!) and are also in general protected from bactericidal antibiotic stress (persistence). 4/n

These strains constitutively hydrolyze ATP (pF1) or NADH (pNOX), creating ATP or NADH sinks in these cells. These in turn induce 'bioenergetic stress' in which the cells are always struggling to meet their energetic demands. 3/n

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Barry generated a genetic model system (frequently used by the metabolic engineering community) involving E coli cells over-expressing ATP synthase F1 complex genes (pF1) or heterologously expressing NADH oxidase from Streptococcus (pNOX). 2/n

Bioenergetic stress potentiates antimicrobial resistance and persistence - Nature Communications

I'm thrilled to share the newest paper from the Yang Lab! Ever wonder how bacterial metabolism affects antibiotic resistance #AMR? In this study, Barry Li, a former MD/PhD student in the lab, took on this question using a systems and #synthetic_biology approach. 1/n www.nature.com/articles/s41...

nature.com

The bactericidal action of some antibiotics is associated with increased ATP consumption, cellular respiration, and reactive oxygen species formation. Here, Li et al. show that constitutive hydrolysis...

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Jason Yang @jasonyanglab.org · 14/05/2025

Honored to receive this year's Young Investigator Award from our local ASM branch!

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Jason Yang @jasonyanglab.org · 14/05/2025

Yang Lab had a terrific time at Rutgers' Biomedical Health Informatics and Artificial Intelligence Symposium yesterday. Great jobs by Yiqi Yan, Oliver Gu, and Reuven Rosen who presented on their work!

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Jason Yang @jasonyanglab.org · 06/05/2025

Our undergraduate machine learning maestro Edson Petry gave a terrific research presentation this afternoon at the Rutgers Pathways for Junior Scientists Research Program! #Rutgers #NJMS

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Jason Yang @jasonyanglab.org · 04/05/2025

Would you mind adding me too please? Thanks in advance!

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Jason Yang @jasonyanglab.org · 24/04/2025

I'm so proud of my technician Lia Goodwin who presented a poster at her first conference at the CSHL Systems Immunology meeting yesterday!

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Terrific work by Ethan Bustad, Edson Petry, Oliver Gu, Braden Griebel, and Tige Rustad and wonderful support from our collaborator David Sherman (U Washington)! @rutgershealth.org 6/6

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We are now using this work as a launching point for studying how individual (clinical) strains survive host and antibiotic stress and are eager to collaborate if you have some interesting phenotypes that you think are geneically regulated! 5/n

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We found that transcription factor activities are better predictors of fitness under hypoxia than TF expression alone. Moreover, these analyses demonstrated that interpretable machine learning can reveal transcriptional programs causally regulating fitness under stress. 4/n

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We performed gene regulatory network analyses to directly infer transcription factor activities from gene expression profiles. Using data from a TF over expression screen (TRIP), we trained an interpretable machine learning model that predicts Mtb fitness from RNA expression. 3/n

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Pathogens live in hostile environments and must activate transcriptional stress response programs to survive exogenous stressors. In work led by Ethan Bustad, we sought to study Mtb fitness under hypoxic stress using systems biology approaches. 2/n

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Frontiers | Predicting fitness in Mycobacterium tuberculosis with transcriptional regulatory network-informed interpretable machine learning

Ever wonder how Mycobacterium #tuberculosis deals with stressful environments? I'm pleased to share that in a second piece of good news this week, our recent work in collaboration with Shuyi Ma (Seattle Children's) was published at Frontiers in Tuberculosis. 1/n www.frontiersin.org/journals/tub...

frontiersin.org

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Jason Yang @jasonyanglab.org · 02/04/2025

I am thrilled to share that our rock star MD/PhD student Barry Li successfully defended his PhD today entitled "Bioenergetic stress potentiates antimicrobial resistance evolution and persistence"! Barry is our first student to finish his PhD and I am so incredibly proud of him!

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Jason Yang @jasonyanglab.org · 18/11/2024

👋 Can I please join also?

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Jason Yang @jasonyanglab.org · 17/11/2024

👋 I'd love to be added too!

Jason Yang @jasonyanglab.org · 14/11/2024

could you please add me? id love to join!

We're grateful for our wonderful collaborators including Shuyi Ma and Greg Cook! 8/8

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This work also highlights the importance of microbiological basic science in studying infectious disease phenotypes and the utility of systems biology approaches (including network modeling and genetic screening) for revealing new mechanisms. 7/n

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In particular, we found INH-resistant Mtb to be vulnerable to protein translation inhibitors, including linezolid. Together, these papers provide several new mechanistic insights into #mycobacterial physiology that we think provide valuable new drug targets. 6/n

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In accompanying work led by Cecilia Wang in Matt McNeil's lab at the University of @otago, we found via CRISPRi that catalase deficiency induces several druggable vulnerabilities that may be targeted by future antibiotics to combat MDR-TB. 5/n

and defects in folate biosynthesis. We discovered these mechanisms hold for both laboratory and clinical strains. 4/n

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Using #systemsbiology approaches, we discovered BDQ hypersensitivity in INH-resistant and MDR cells is caused by potentiated BDQ-induced ROS generation, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, 3/n