Biology subjects

Delaney, O.

Publications and source records attributed to Delaney, O..

3 recordsLinked to original sources

bioRxiv2024

Optimal antimicrobial dosing combinations when drug-resistance mutation rates differ

Given the ongoing antimicrobial resistance crisis, it is imperative to develop dosing regimens optimised to avoid the evolution of resistance. The rate at which bacteria acquire resistance-conferring mutations to different antimicrobial drugs spans multiple orders of magnitude. By using a mathematical model and computer simulations, we show that knowledge of relative mutation rates can meaningfully inform the optimal combination of two drugs in a treatment regimen. We demonstrate that under plausible assumptions there is a linear relationship in log-log space between the drug A:drug B dose ratio that maximises the chance of treatment success and the ratio of their mutation rates. This power law relationship holds for bacteriostatic and bactericidal drugs. If borne out empirically, these findings suggest there might be significant room to further optimise antimicrobial dosing strategies.

evolutionary biology↗

bioRxiv2023

Drug mode of action and resource constraints modulate antimicrobial resistance evolution

One of the key characteristics of an antibiotic drug is its mode of action: bacteriostatic or bactericidal. The effect of drug mode of action on the evolution of resistance has been surprisingly underinvestigated to date. We present a theoretical model comparing the efficacy of bacteriostatic and bactericidal drugs, and drugs of intermediate type, at preventing the evolutionary rescue of an initially susceptible bacterial population in a patient. Our results suggest that in resource-abundant environments bacteriostatic drugs are best, as they constrain cell divisions and thus cause fewer resistance mutations to occur. When multiple drugs are employed, using one bacteriostatic and one bactericidal drug is usually optimal, because the cell division rate cannot fall below zero, so there are diminishing returns to bacteriostatic activity from two drugs. We also provide a web-based simulation engine for other researchers to intuitively explore related dynamics without requiring programming expertise.

evolutionary biology↗

bioRxiv2023

Frequent, infinitesimal bottlenecks maximize the rate of microbial adaptation

Serial passaging is a fundamental technique in experimental evolution. The choice of bottleneck severity and frequency poses a dilemma: longer growth periods allow beneficial mutants to arise and grow over more generations, but simultaneously necessitate more severe bottlenecks with a higher risk of those same mutations being lost. Short growth periods require less severe bottlenecks, but come at the cost of less time between transfers for beneficial mutations to establish. The standard laboratory protocol of 24-hour growth cycles with severe bottlenecking has logistical advantages for the experimenter but limited theoretical justification. Here we demonstrate that contrary to standard practice, the rate of adaptive evolution is maximized when bottlenecks are frequent and small, indeed infinitesimally so in the limit of continuous culture. This result derives from revising key assumptions underpinning previous theoretical work, including changing the metric of optimization to incorporate experiment runtime, and using a full binomial distribution for bottlenecking, rather than a Poisson approximation. We also show that adding resource constraints and clonal interference to the model leaves the qualitative results unchanged. Implementing these findings will require liquid-handling robots to perform frequent bottlenecks, or chemostats for continuous culture. Further innovation in and adoption of these technologies has the potential to accelerate the rate of discovery in experimental evolution.

genetics↗