Antibiotic Tolerance and persistence in structured environments

Since their introduction in clinic, antibiotics have changed favorably the outcome of infectious diseases caused by bacteria. However, the constant emergence and dissemination of antibiotic resistance within bacterial populations is threatening healthcare practices worldwide. In addition to antibiotic resistance, which is defined by the ability of bacteria to grow in presence of antibiotics, antibiotic therapy is also compromised by antibiotic tolerance and persistence. Both phenomena differ from antibiotic resistance as they don’t affect the minimal concentration inhibiting bacterial growth (MIC) and, unlike antibiotic resistance, they are not genetically heritable. They are characterized by a reduction of the killing efficacy of bactericidal antibiotics and can be seen either at the population level (tolerance) or within subpopulations (persistence). While Persistence was reported nearly 75 years ago it has been overshadowed by the more prominent narrative of antibiotic resistance. However, it represents relevant ways where bacteria can escape treatments. Current understanding of its mechanisms and its relevance in terms of a potential cause of treatment failure and recalcitrant infections demonstrates that it is a complex phenomenon involving bacterial cells metabolism, their environment, and genetic elements.
Our project aims to characterize the molecular mechanisms of persistence of Escherichia coli clinical isolates to understand how it impairs antibiotic efficacy. We use a combination of single cell and population studies to investigate how heterogeneity in genes expression and physiological states can affect efficacy of antibiotics.
We use bacteria living within colony or in micro-aggregates as models to test how the structuration of the environment affects antibiotic activity. These models are close to biofilms, where bacteria live in heterogeneous conditions defining constant creation of various new microhabitats and present high levels of stress resilience.
This project will identify sets of conditions altering maximal antibiotic activity in order to comprehend antibiotic treatment failure which may help to devise new or better therapeutic strategies.


Publications :

1. Su WL, Bredèche MF, Dion S, Dauverd J, Condamine B, Gutierrez A, et al. TisB Protein Protects Escherichia coli Cells Suffering Massive DNA Damage from Environmental Toxic Compounds. Mbio. 2022;13(2):e00385-22.
2. Lobritz MA, Andrews IW, Braff D, Porter CB, Gutierrez A, Furuta Y, et al. Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality. Cell Chemical Biology. 2022;29(2):276‑86.
3. Atze H, Liang Y, Hugonnet JE, Gutierrez A, Rusconi F, Arthur M. Heavy isotope labeling and mass spectrometry reveal unexpected remodeling of bacterial cell wall expansion in response to drugs. eLife. 2022;11:e72863.
4. Decrulle AL, Frénoy A, Meiller-Legrand TA, Bernheim A, Lotton C, Gutierrez A, et al. Engineering gene overlaps to sustain genetic constructs in vivo. PLoS computational biology. 2021;17(10):e1009475.
5. Stokes JM*, Gutierrez A*, Lopatkin AJ, Andrews IW, French S, Matic I, et al. A multiplexable assay for screening antibiotic lethality against drug-tolerant bacteria. Nature methods. 2019;16(4):303.
6. Gutierrez A, Stokes JM, Matic I. Our evolving understanding of the mechanism of quinolones. Antibiotics. 2018;7(2):32.
7. Meylan S, Porter CB, Yang JH, Belenky P, Gutierrez A, Lobritz MA, et al. Carbon sources tune antibiotic susceptibility in Pseudomonas aeruginosa via tricarboxylic acid cycle control. Cell chemical biology. 2017;24(2):195‑206.
8. Gutierrez A, Jain S, Bhargava P, Hamblin M, Lobritz MA, Collins JJ. Understanding and sensitizing density-dependent persistence to quinolone antibiotics. Molecular Cell. 2017;68(6):1147‑54.
9. Cohen NR, Ross CA, Jain S, Shapiro RS, Gutierrez A, Belenky P, et al. A role for the bacterial GATC methylome in antibiotic stress survival. Nature genetics. 2016;48(5):581‑6.
10. Lobritz MA, Belenky P, Porter CB, Gutierrez A, Yang JH, Schwarz EG, et al. Antibiotic efficacy is linked to bacterial cellular respiration. Proceedings of the National Academy of Sciences. 2015;112(27):8173‑80.
11. Laureti L, Matic I, Gutierrez A. Bacterial responses and genome instability induced by subinhibitory concentrations of antibiotics. Antibiotics. 2013;2(1):100‑14.
12. Gutierrez A, Laureti L, Crussard S, Abida H, Rodríguez-Rojas A, Blázquez J, et al. β-Lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity. Nature communications. 2013;4(1):1‑9.
13. Gutierrez A, Elez M, Clermont O, Denamur E, Matic I. Escherichia coli YafP protein modulates DNA damaging property of the nitroaromatic compounds. Nucleic acids research. 2011;39(10):4192‑201.