Designing targeted perturbations to drive evolution toward higher drug sensitivity

• Applicant: Dr. Francesca Macaluso
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556950884

The insurgence of bacterial resistance to antibiotics is a major public health problem and calls for new strategies able to counteract the insurgence of resistance mechanisms. The efficacy of antibiotics is often measured via the dose-response curves that describe how bacterial growth changes as a function of the antibiotic concentration. The steepness of the dose-response curve varies drastically between different antibiotics and, in rare cases, can acquire an uncommon non-monotonic shape. This is the case for trimethoprim (TMP), an antibiotic that inhibits folic acid synthesis. When bacterial growth is impaired through non-antibiotic perturbations, such as nutrient limitation or increased protein burden, the efficacy of TMP is decreased. Strikingly, when growth is more severely impaired by a stronger nutrient deprivation, the addition of TMP becomes paradoxically beneficial and partially rescues growth, resulting in the uncommon non-monotonic shape of the dose-response curve. The identification of growth conditions where the antibiotics can become beneficial potentially allows the development of evolutionary traps where cells are “forced” to select for, rather than against, antibiotic uptake/activity. We aim to systematically identify non-antibiotic perturbations that strongly impair growth and investigate whether the addition of a broad range of antibiotics can become beneficial in such adverse growth conditions. Upon validation of such paradoxical scenarios, we aim to perform evolution experiments in the presence of the detrimental perturbation along with the beneficial antibiotic. We finally aim to characterize the evolved bacteria and test if they acquire higher drug sensitivity and through what molecular mechanisms. Such evolutionary strategies aimed at increasing, rather than decreasing, the sensitivity to antibiotics, may provide the basis for new therapeutic approaches able to slow the rise of antibiotic resistance or even to re-sensitize bacteria.

• DFG Programme: WBP Position