Convection shapes the trade-off between antibiotic efficacy and the selection for resistance in spatial gradients

Abstract

Since penicillin was discovered about 90 years ago, we have become used to using drugs to eradicate unwanted pathogenic cells. However, using drugs to kill bacteria, viruses or cancer cells has the serious side effect of selecting for mutant types that survive the drug attack. A key question therefore is how one could eradicate as many cells as possible for a given acceptable risk of drug resistance evolution. We address this general question in a model of drug resistance evolution in spatial drug gradients, which recent experiments and theories have suggested as key drivers of drug resistance. Importantly, our model takes into account the influence of convection, resulting for instance from blood flow. Using stochastic simulations, we study the fates of individual resistance mutations and quantify the trade-off between the killing of wild-type cells and the rise of resistance mutations: shallow gradients and convection into the antibiotic region promote wild-type death, at the cost of increasing the establishment probability of resistance mutations. We can explain these observed trends by modeling the adaptation process as a branching random walk. Our analysis reveals that the trade-off between death and adaptation depends on the relative length scales of the spatial drug gradient and random dispersal, and the strength of convection. Our results show that convection can have a momentous effect on the rate of establishment of new mutations, and may heavily impact the efficiency of antibiotic treatment.

Environmental disorder can tip the population genetics of range expansions

“…However, the effects of such environmental heterogeneity, which can be viewed as a source of extrinsic noise, on evolutionary dynamics in microbial populations have received much less attention. Efforts have concentrated mostly on simple temporal and spatial gradients in antibiotic concentration, which have been shown to facilitate the emergence of resistance in shaken cultures [37], microfluidic devices [51] and on agar plates [4], as predicted by theory [20,23,[25][26][27].…”

Tuning Spatial Profiles of Selection Pressure to Modulate the Evolution of Drug Resistance

“…At the same time, evolutionary biologists have long recognized resistance as a fundamentally stochastic process governed by the complex interplay between microbial ecology and evolutionary selection. The last decade, in particular, has seen a significant surge in efforts to develop and understand evolution-based treatment strategies to forestall resistance [5–16]. While the vast majority of this work focuses on spatially homogeneous environments, a number of recent studies, both theoretical and experimental, have demonstrated that spatial heterogeneity in drug concentration can dramatically alter the evolutionary dynamics leading to resistance [16–24].…”

“…The last decade, in particular, has seen a significant surge in efforts to develop and understand evolution-based treatment strategies to forestall resistance [5–16]. While the vast majority of this work focuses on spatially homogeneous environments, a number of recent studies, both theoretical and experimental, have demonstrated that spatial heterogeneity in drug concentration can dramatically alter the evolutionary dynamics leading to resistance [16–24]. On a practical level, the picture that emerges is somewhat bleak, as resistance evolution is dramatically accelerated in the presence of spatial gradients in drug concentration [18–20, 22–24] or heterogeneous drug penetration [17, 21].…”

Tuning Spatial Profiles of Selection Pressure to Modulate the Evolution of Resistance

“…At the same time, evolutionary biologists have long recognized resistance as a fundamentally stochastic process governed by the complex interplay between microbial ecology and evolutionary selection. The last decade, in particular, has seen a significant surge in efforts to develop and understand evolution-based treatment strategies to forestall resistance [5][6][7][8][9][10][11][12][13][14][15][16]. While the vast majority of this work focuses on spatially homogeneous environments, a number of recent studies, both theoretical and experimental, have demonstrated that spatial heterogeneity in drug concentration can dramatically alter the evolutionary dynamics leading to resistance [16][17][18][19][20][21][22][23][24].…”

“…The last decade, in particular, has seen a significant surge in efforts to develop and understand evolution-based treatment strategies to forestall resistance [5][6][7][8][9][10][11][12][13][14][15][16]. While the vast majority of this work focuses on spatially homogeneous environments, a number of recent studies, both theoretical and experimental, have demonstrated that spatial heterogeneity in drug concentration can dramatically alter the evolutionary dynamics leading to resistance [16][17][18][19][20][21][22][23][24]. On a practical level, the picture that emerges is somewhat bleak, as resistance evolution is dramatically accelerated in the presence of spatial gradients in drug concentration [18][19][20][22][23][24] or heterogeneous drug penetration [17,21].…”