Systems Biology of Bacterial Antibiotic Resistance Mechanisms
Emerging Team
Our laboratory studies the molecular mechanisms of antibiotic tolerance — the ability of bacterial populations to survive, but not grow, for prolonged periods upon exposure to lethal antibiotic concentrations, in the absence of resistance. Working in Mycobacterium tuberculosis and Gram-negative bacteria, notably Klebsiella pneumoniae, we ask not only whether a drug stops bacterial growth, but how fast it kills. Because tolerance can arise through a large number of distinct physiological routes, we focus on identifying molecular convergence points — nexuses where multiple slow-killing mechanisms coalesce — that can be prioritised for drug development. Ultimately, we aim to define mechanism-convergent, drug-agnostic determinants of tolerance across bacterial species, for improved treatment outcomes and for genomic diagnostics able to anticipate resistance development.
Lab members
Publications
Fast-growing intracellular Mycobacterium tuberculosis populations evade antibiotic treatment. Nathan J. Day, Baptiste Pradel, et al., Nature Communications 2026. DOI: 10.1038/s41467-026-75915-8
Mtb-Timer: a fluorescent reporter to visualize Mycobacterium tuberculosis replication and antibiotic responses. Víctor Campo-Pérez, Chak Hon Luk, et al., mSystems 2026. DOI: 10.1128/msystems.01796-25
Alanine dependence of trans-translation contributes to riboregulation of mycobacterial antibiotic recalcitrance genes. Andrea Majstorović, Hélène Botella, et al., bioRxiv 2025. DOI: 10.1101/2025.10.10.681568
Reframing antimicrobial resistance as a continuous spectrum of manifestations. Sarah M. Schrader, Hélène Botella, et al., Current Opinion in Microbiology 2023. DOI: 10.1016/j.mib.2022.102259
Multiform antimicrobial resistance from a metabolic mutation. Sarah M. Schrader, Hélène Botella, et al., Science Advances 2021. DOI: 10.1126/sciadv.abh2037
Nonredundant functions of Mycobacterium tuberculosis chaperones promote survival under stress. Alexa P. Harnagel, Landys A. Lopez Quezada, et al., Molecular Microbiology 2020. DOI: 10.1111/mmi.14615
Biology of antimicrobial resistance and approaches to combat it. Sarah M. Schrader, Julien Vaubourgeix, et al., Science Translational Medicine 2020. DOI: 10.1126/scitranslmed.aaz6992
Intestinal Bile Acids Induce a Morphotype Switch in Vancomycin-Resistant Enterococcus that Facilitates Intestinal Colonization. Peter T. McKenney, Jinyuan Yan, et al., Cell Host & Microbe 2019. DOI: 10.1016/j.chom.2019.03.008
Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition. Elaine A. Ballinger, John Mosior, et al., Science 2019. DOI: 10.1126/science.aau8959
Persistent Mycobacterium tuberculosis infection in mice requires PerM for successful cell division. Ruojun Wang, Kaj M. Kreutzfeldt, et al., eLife 2019. DOI: 10.7554/elife.49570
Building Walls: Work That Never Ends. Hélène Botella, Julien Vaubourgeix, Trends in Microbiology 2018. DOI: 10.1016/j.tim.2018.11.006
Targeting the Proteostasis Network for Mycobacterial Drug Discovery. Tania J. Lupoli, Julien Vaubourgeix, et al., ACS Infectious Diseases 2018. DOI: 10.1021/acsinfecdis.7b00231
Depleting Mycobacterium tuberculosis of the transcription termination factor Rho causes pervasive transcription and rapid death. Laure Botella, Julien Vaubourgeix, et al., Nature Communications 2017. DOI: 10.1038/ncomms14731
Mycobacterium tuberculosis protease MarP activates a peptidoglycan hydrolase during acid stress. Hélène Botella, Julien Vaubourgeix, et al., The EMBO Journal 2017. DOI: 10.15252/embj.201695028
Distinct Spatiotemporal Dynamics of Peptidoglycan Synthesis between Mycobacterium smegmatis and Mycobacterium tuberculosis. Hélène Botella, Guangli Yang, et al., mBio 2017. DOI: 10.1128/mbio.01183-17
Stressed Mycobacteria Use the Chaperone ClpB to Sequester Irreversibly Oxidized Proteins Asymmetrically Within and Between Cells. Julien Vaubourgeix, Gang Lin, et al., Cell Host & Microbe 2015. DOI: 10.1016/j.chom.2014.12.008
Disruption of an M. tuberculosis Membrane Protein Causes a Magnesium-dependent Cell Division Defect and Failure to Persist in Mice. Nichole Goodsmith, Xinzheng Victor Guo, et al., PLOS Pathogens 2015. DOI: 10.1371/journal.ppat.1004645
N,C-Capped Dipeptides with Selectivity for Mycobacterial Proteasome over Human Proteasomes: Role of S3 and S1 Binding Pockets. Gang Lin, Tamutenda Chidawanyika, et al., Journal of the American Chemical Society 2013. DOI: 10.1021/ja400021x
A Common Mechanism of Inhibition of the Mycobacterium tuberculosis Mycolic Acid Biosynthetic Pathway by Isoxyl and Thiacetazone. Anna E. Grzegorzewicz, Jana Korduláková, et al., Journal of Biological Chemistry 2012. DOI: 10.1074/jbc.m112.400994
Deciphering sulfoglycolipids of Mycobacterium tuberculosis. Emilie Layre, Diane Cala‐De Paepe, et al., Journal of Lipid Research 2011. DOI: 10.1194/jlr.m013482
Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ. Jichan Jang, Alexandre Stella, et al., Microbiology 2010. DOI: 10.1099/mic.0.038133-0
S-Adenosyl-N-decyl-aminoethyl, a Potent Bisubstrate Inhibitor of Mycobacterium tuberculosis Mycolic Acid Methyltransferases. Julien Vaubourgeix, F. Bardou, et al., Journal of Biological Chemistry 2009. DOI: 10.1074/jbc.m809599200
Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence. Pascale Peyron, Julien Vaubourgeix, et al., PLoS Pathogens 2008. DOI: 10.1371/journal.ppat.1000204
