About
Sabine Ehrt, Ph.D., is the Chair of the Department of Microbiology and Immunology at Weill Cornell Medicine and a Professor of Microbiology and Immunology. Her research focuses on the pathogenesis of tuberculosis, specifically investigating how Mycobacterium tuberculosis establishes and maintains chronic infections, resists host defenses, and develops drug resistance. Her work aims to aid the development of new chemotherapies and vaccines by analyzing the molecular mechanisms that enable the bacteria to persist and evade immune responses. She applies molecular genetics to identify vulnerabilities in the bacteria that could be targeted to improve treatment outcomes, especially in cases of latent infection and multi-drug resistant strains. Additionally, her research explores host immune factors involved in controlling M. tuberculosis and seeks strategies to generate more effective TB vaccines.
Research topics
- Biology
- Biochemistry
- Evolutionary biology
- Genetics
- Computational biology
- Cell biology
Selected publications
Communications Biology · 2026-04-18
articleOpen accessThe human pathogen Mycobacterium tuberculosis (Mtb) thrives in lipid-rich microenvironments. A strong body of evidence demonstrated that, during infection, Mtb utilizes long-chain fatty acids (LCFA) as a preferred carbon source. However, LCFA also have antimicrobial properties. Mtb must therefore employ mechanisms to utilize LCFA while mitigating their toxicity. Using transposon sequencing (TnSeq), we defined the Mtb LCFA resistome as comprising 38 genes. Surprisingly, LCFA resistance requires diverse metabolic pathways, indicating pleiotropic effects of LCFA on Mtb physiology. We investigated the function of the TnSeq top-hit, the universal stress protein TB15.3, and demonstrate that it participates in a "metabolic brake" mechanism restricting LCFA uptake and catabolism to prevent membrane hyperpolarization. TB15.3 absence caused Mtb to lose viability during chronic infection in mice and in an in vitro caseum model. Our work highlights Mtb LCFA resistance mechanisms as an important host adaptation and a promising target space for drug development.
Microbiology Resource Announcements · 2025-07-11
articleOpen accessABSTRACT Mycobacterium tuberculosis, the causative agent of tuberculosis, remains the leading global infectious disease killer. Adaptation of Mycobacterium tuberculosis to acidic niches within the host during infection is vital to establish the disease. Here, we present a high-density transposon mutant sequencing library data set identifying genetic determinants of acid growth arrest to serve as a resource.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-15 · 3 citations
preprintOpen accessIn an era of increasing resistance, new and effective strategies are needed for antibiotic discovery. Whole-cell active screens yield candidate compounds lacking mechanism-of-action (MOA) information and thus do not provide biological insight for prioritization. We previously reported PROSPECT ( PR imary screening O f S trains to P rioritize E xpanded C hemistry and T argets), an antimicrobial discovery strategy that measures chemical-genetic interactions between small molecules and a pool of Mycobacterium tuberculosis mutants, each depleted of a different essential protein target. PROSPECT facilitates efficient hit prioritization by simultaneously identifying whole-cell active compounds with high sensitivity and providing early insights into their MOA. Here, we report a reference-based approach to infer MOA from often complex PROSPECT data. For this aim, we curated a reference set of 437 compounds with published, annotated MOA and known or suspected antitubercular activity, and applied PROSPECT to it. We then developed P erturbagen CL ass (PCL) analysis, a computational method that predicts MOA by comparing chemical-genetic interaction profiles of unknown compounds to those of this reference set. In leave-one-out cross-validation, PCL analysis correctly predicted MOA with 70% sensitivity and 75% precision. When applied to 75 antitubercular leads with known MOA previously reported by GlaxoSmithKline (GSK), PCL analysis similarly achieved 69% sensitivity and 87% precision. We also analyzed 98 GSK compounds lacking MOA information, predicting 60 of them to act via a reference MOA, and followed up with functional validation of 29 compounds predicted to target respiration-related MOAs. Finally, we applied PROSPECT and PCL analysis to ~5,000 compounds from larger unbiased libraries that had not been preselected for antitubercular activity. PCL analysis identified a novel scaffold lacking wild-type activity but predicted to inhibit respiration via QcrB, and we confirmed this prediction while chemically optimizing this scaffold to achieve wild-type activity. PCL analysis of PROSPECT data thus enables rapid MOA assignment and hit prioritization, advancing the discovery of new, potent antitubercular compounds.
Nature Microbiology · 2025-01-10 · 10 citations
articleOpen accessbioRxiv (Cold Spring Harbor Laboratory) · 2025-07-08 · 1 citations
preprintOpen accessSenior authorCorrespondingAbstract The intrinsic drug resistance of Mycobacterium tuberculosis (Mtb) is a major barrier to effective tuberculosis (TB) treatment, largely due to its complex, impermeable cell envelope. We identified a periplasmic protein complex comprising FecB and Rv3035 that is essential for maintaining envelope integrity and mediating intrinsic multidrug resistance in Mtb. FecB interacts with Rv3035, forming a stable heterodimer that associates with the cell envelope biosynthesis protein AftB. We report the structures of Rv3035 alone and in complex with FecB and identify critical residues for complex formation and function. Co-essentiality and genetic interaction analyses support a functional link between FecB, Rv3035 and AftB, an arabinofuranosyltransferase which synthesizes arabinogalactan and lipoarabinomannan. Loss of FecB or Rv3035 disrupted AftB-mediated arabinan synthesis, suggesting that these proteins support AftB’s enzymatic activity. Importantly, FecB is required for Mtb virulence in mice, underscoring its physiological relevance. These findings highlight FecB, Rv3035 and AftB as promising therapeutic targets.
Nature Communications · 2025-11-03 · 3 citations
articleOpen accessWe previously reported an antibiotic discovery screening platform that identifies whole-cell active compounds with high sensitivity while simultaneously providing mechanistic insight, necessary for hit prioritization. Named PROSPECT, (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets), this platform measures chemical-genetic interactions between small molecules and pooled Mycobacterium tuberculosis mutants, each depleted of a different essential protein. Here, we introduce Perturbagen CLass (PCL) analysis, a computational method that infers a compound's mechanism-of-action (MOA) by comparing its chemical-genetic interaction profile to those of a curated reference set of 437 known molecules. In leave-one-out cross-validation, we correctly predict MOA with 70% sensitivity and 75% precision, and achieve comparable results (69% sensitivity, 87% precision) with a test set of 75 antitubercular compounds with known MOA previously reported by GlaxoSmithKline (GSK). From 98 additional GSK antitubercular compounds with unknown MOA, we predict 60 to act via a reference MOA and functionally validate 29 compounds predicted to target respiration. Finally, from a set of ~5,000 compounds from larger unbiased libraries, we identify a novel QcrB-targeting scaffold that initially lacked wild-type activity, experimentally confirming this prediction while chemically optimizing this scaffold. PCL analysis of PROSPECT data enables rapid MOA assignment and hit prioritization, streamlining antimicrobial discovery.
Nature Microbiology · 2025-01-10 · 16 citations
articleOpen accessAbstract Human challenge experiments could accelerate tuberculosis vaccine development. This requires a safe Mycobacterium tuberculosis (Mtb) strain that can both replicate in the host and be reliably cleared. Here we genetically engineered Mtb strains encoding up to three kill switches: two mycobacteriophage lysin operons negatively regulated by tetracycline and a degron domain–NadE fusion, which induces ClpC1-dependent degradation of the essential enzyme NadE, negatively regulated by trimethoprim. The triple-kill-switch (TKS) strain showed similar growth kinetics and antibiotic susceptibilities to wild-type Mtb under permissive conditions but was rapidly killed in vitro without trimethoprim and doxycycline. It established infection in mice receiving antibiotics but was rapidly cleared upon cessation of treatment, and no relapse was observed in infected severe combined immunodeficiency mice or Rag −/− mice. The TKS strain had an escape mutation rate of less than 10 −10 per genome per generation. These findings suggest that the TKS strain could be a safe, effective candidate for a human challenge model.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-14
preprintOpen accessCorrespondingABSTRACT The human pathogen Mycobacterium tuberculosis (Mtb) thrives in lipid-rich microenvironments. Long-chain fatty acids (LCFA) are some of the most abundant lipids encountered by Mtb during infection. Mtb has evolved to utilize LCFA as a preferred carbon source, however, LCFA are also known to be potent antimicrobials. Mtb must therefore employ mechanisms to utilize LCFA as a carbon source while avoiding its bactericidal properties. We used transposon sequencing (TnSeq) to define a Mtb LCFA resistome, and found it to be composed by 38 genes. Surprisingly, Mtb requires a diverse set of metabolic pathways to avoid LCFA toxicity, indicating pleiotropic effects of LCFA in Mtb metabolism. As a functional follow-up on the TnSeq screen, we investigated the function of the universal stress protein TB15.3 in LCFA metabolism and during infection. We show that TB15.3 acts as a “metabolic break” for LCFA uptake and catabolism, avoiding deleterious membrane hyperpolarization. This was associated with loss of viability in the chronic phase of infection in mice and in an in vitro caseum model. Our work highlights Mtb LCFA resistance mechanisms as an important adaptation to the host and a promising target space to be exploited for drug development.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-31 · 1 citations
preprintOpen accessSenior authorCorrespondingAlveolar macrophages (AMs) are the first immune cells to encounter Mycobacterium tuberculosis (Mtb) in the lungs, but they frequently fail to eliminate this causative agent of tuberculosis (TB), allowing Mtb to persist or replicate. Interstitial macrophages (IMs) are recruited to restrict Mtb growth and limit immune evasion. While IMs have been implicated in the control of acute Mtb infection, their role during latent tuberculosis infection (LTBI) has not yet been explored. We hypothesized that IMs contribute to maintaining latency and that their depletion during LTBI would promote Mtb reactivation, leading to TB relapse and disease. To test this, we utilized our previously established mouse model of paucibacillary Mtb infection that mimics aspects of LTBI in humans to selectively deplete IMs during the latent phase. IM depletion led to TB relapse in 26% of mice compared to 2% in control mice. The transitory depletion of this macrophage subset transiently affected both pulmonary macrophage and neutrophil populations. Mice that relapsed exhibited an increased proportion of pro-inflammatory IMs and elevated concentrations of G-CSF, GM-CSF, IL3, IL-12, IL-13, IL-17A and KC in the lung. These findings indicate that IMs play a critical role in controlling latent Mtb and preventing TB relapse.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-15
preprintOpen accessAbstract In mycobacteria, the protein EtfD is thought to link β-oxidation of fatty acids with the electron transport chain, two processes that have attracted attention as targets for therapeutics to treat tuberculosis (TB) and other mycobacterial infections. It has been proposed that targeting β- oxidation could shorten treatment duration by killing non-replicating Mycobacterium tuberculosis within granulomas in the lungs. Here we show that Mycobacterium smegmatis , a fast growing and nonpathogenic model for energy metabolism in M. tuberculosis , relies on EtfD for extracting energy from β-oxidation. Electron cryomicroscopy allowed structure determination of M. smegmatis EtfD, revealing an unusual linear [3Fe-4S] cluster that has not been seen in other protein structures, but which resembles the catalytic noncubane [4Fe-4S] clusters in heterodisulfide reductases. The structure suggests how EtfD transfers electrons from β-oxidation to the electron transport chain. We devised an assay that couples EtfD activity to a fluorescent readout of proton pumping by the electron transport chain, which can be used to identify compounds that block mycobacteria from using β-oxidation to power oxidative phosphorylation.
Recent grants
NIH · $3.0M · 2016
Conditional Expression of Mycobacterial Genes
NIH · $7.2M · 2006–2024
Biomarkers of PZA activity and it's target populations
NIH · $84.8M · 2014–2021
NIH · $2.8M · 2014
NIH · $2.3M · 2007
Frequent coauthors
- 116 shared
Dirk Schnappinger
Cornell University
- 44 shared
Kyu Y. Rhee
Weill Cornell Medicine
- 34 shared
Carl Nathan
Cornell University
- 31 shared
Carolina Trujillo
Hospital Nacional Cayetano Heredia
- 22 shared
Thomas R. Ioerger
- 19 shared
Véronique Dartois
Hackensack Meridian Health
- 17 shared
Anisha Zaveri
Cornell University
- 17 shared
Hongwei Su
Shunyi Hospital of Beijing Traditional Chinese Medicine Hospital
Labs
Education
- 1994
PhD, Microbiology
Friedrich-Alexander-Universität Erlangen-Nürnberg
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