Mathematical modelling of antibiotic interaction on evolution of antibiotic resistance: an analytical approach

PeerJ. 2024 Feb 26:12:e16917. doi: 10.7717/peerj.16917. eCollection 2024.

Abstract

Background: The emergence and spread of antibiotic-resistant pathogens have led to the exploration of antibiotic combinations to enhance clinical effectiveness and counter resistance development. Synergistic and antagonistic interactions between antibiotics can intensify or diminish the combined therapy's impact. Moreover, these interactions can evolve as bacteria transition from wildtype to mutant (resistant) strains. Experimental studies have shown that the antagonistically interacting antibiotics against wildtype bacteria slow down the evolution of resistance. Interestingly, other studies have shown that antibiotics that interact antagonistically against mutants accelerate resistance. However, it is unclear if the beneficial effect of antagonism in the wildtype bacteria is more critical than the detrimental effect of antagonism in the mutants. This study aims to illuminate the importance of antibiotic interactions against wildtype bacteria and mutants on the deacceleration of antimicrobial resistance.

Methods: To address this, we developed and analyzed a mathematical model that explores the population dynamics of wildtype and mutant bacteria under the influence of interacting antibiotics. The model investigates the relationship between synergistic and antagonistic antibiotic interactions with respect to the growth rate of mutant bacteria acquiring resistance. Stability analysis was conducted for equilibrium points representing bacteria-free conditions, all-mutant scenarios, and coexistence of both types. Numerical simulations corroborated the analytical findings, illustrating the temporal dynamics of wildtype and mutant bacteria under different combination therapies.

Results: Our analysis provides analytical clarification and numerical validation that antibiotic interactions against wildtype bacteria exert a more significant effect on reducing the rate of resistance development than interactions against mutants. Specifically, our findings highlight the crucial role of antagonistic antibiotic interactions against wildtype bacteria in slowing the growth rate of resistant mutants. In contrast, antagonistic interactions against mutants only marginally affect resistance evolution and may even accelerate it.

Conclusion: Our results emphasize the importance of considering the nature of antibiotic interactions against wildtype bacteria rather than mutants when aiming to slow down the acquisition of antibiotic resistance.

Keywords: Antibiotic; Antibiotic interaction; Differential equation; Equilibrium solutions.

MeSH terms

  • Anti-Bacterial Agents* / pharmacology
  • Bacteria
  • Bacterial Infections*
  • Drug Resistance, Microbial / genetics
  • Humans
  • Models, Theoretical

Substances

  • Anti-Bacterial Agents

Grants and funding

This work was funded by TUBITAK, 2232—International Fellowship for Outstanding Researchers, Project number 118C244. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.