Dr. Hélène Botella - Development of forward genetic methodologies to identify determinants of tolerance to antibiotics

Hélène Botella

Imperial College, London, UK

Development of forward genetic methodologies to identify determinants of tolerance to antibiotics

Antimicrobial resistance (AMR) is the ability of bacteria to avoid or delay being killed by an antibiotic. AMR can manifest in three ways: resistance, tolerance, or high persistence. Tolerance and high persistence complicate treatment of many bacterial infections, including tuberculosis, via contributing to treatment length, treatment failure, disease recurrence, and the emergence of resistance. Therapeutically targeting tolerant and persistent cells could improve outcomes, but the molecular mechanisms underlying tolerance and persistence in bacteria are not well understood. To fill this gap, we developed two forward genetic methods for the isolation of mutants that display tolerance and/or high persistence but not resistance. We are currently applying these two methods in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, and uropathogenic Escherichia coli, which causes urinary tract infections, to unveil the molecular mechanisms by which tolerance and high persistence arise in two human pathogens associated with high rates of relapse of infection.

Selected references

• Botella H, Vaubourgeix J. Building Walls: Work That Never Ends. Trends Microbiol. 2019 27(1):4-7
• Schrader SM, Botella H, Vaubourgeix J. Reframing antimicrobial resistance as a continuous spectrum of manifestations. Curr Opin Microbiol. 2023 72:102259
• Botella H, Vaubourgeix J, Lee MH, Song N, Xu W, Makinoshima H, Glickman MS, Ehrt S. Mycobacterium tuberculosis protease MarP activates a peptidoglycan hydrolase during acid stress. EMBO J. 2017 36(4):536-54
• Botella H, Yang G, Ouerfelli O, Ehrt S, Nathan CF, Vaubourgeix J. Distinct Spatiotemporal Dynamics of Peptidoglycan Synthesis between Mycobacterium smegmatis and Mycobacterium tuberculosis. mBio. 2017 8(5):e01183-17