Biology subjects

Trubenova, B.

Publications and source records attributed to Trubenova, B..

3 recordsLinked to original sources

bioRxiv2026

On repeatability and directionality of collateral effects of drug resistance evolution

Drug resistance evolution is hindering the treatment of various diseases. One possible solution could be exploiting trade-offs in resistance to different, existing drugs. Collateral sensitivity means that resistance to one drug increases susceptibility to another. Contrarily, cross-resistance means that resistance to one drug implies resistance to another. These two collateral effects are, however, not always repeatable, nor are they always independent of drug order, i.e. bidirectional. Understanding what drives repeatability and directionality would help define the clinical applicability of collateral sensitivity and avoid cross-resistance. Nevertheless, the genetic and evolutionary mechanisms causing non-repeatability and unidirectionality patterns are not yet fully understood. In this study, we aim to define which drug concentrations, population dynamics, and genetic architectures cause these patterns of collateral effects. We describe the fewest loci and conditions needed for repeatable and non-repeatable, uni- or bidirectional cross-resistance and collateral sensitivity to occur. We show that increasing drug concentration narrows the set of possible adaptive genotypes and thereby increases repeatability. As for selection regimes, clonal interference can explain unidirectional cross-resistance and can increase repeatability, whereas a strong selection, weak mutation regime increases non-repeatability. Overall, we show how non-repeatability and unidirectionality of collateral effects are not properties solely of a drug pair but also of the selection regime: drug dose and population dynamics. Further studies, combining extensive mathematical modelling with measurements of full dose-response curves for drug pairs with known patterns of collateral effects, are needed to shed more light on this problem. 1 Significance statementPredicting the evolution of multidrug resistance is one of the most pressing challenges in modern evolutionary biology and medicine. On the other hand, exploiting "collateral sensitivity" (where resistance to one drug increases susceptibility to another) is a promising direction for sustainable therapies. Collateral effects are often unpredictable and may depend on the order of drug administration (asymmetry), which hinders their clinical applications. While research traditionally treats collateral effects and their patterns as fixed properties of specific drug pairs, we demonstrate how they are fundamentally shaped by the selection environment.

evolutionary biology↗

bioRxiv2024

Evolution of ivermectin resistance in the nematode model Caenorhabditis elegans: critical influence of population size and unexpected cross-resistance to emodepside

The emergence and spread of anthelmintic resistance represent a major challenge for treating parasitic nematodes, threatening mass-drug control programs in humans and zoonotic species. Currently, experimental evidence to understand the influence of management (e.g., treatment intensity and frequency) and parasite-associated factors (e.g., genetic variation, population size and mutation rates) is lacking. To rectify this knowledge gap, we performed controlled evolution experiments with the model nematode Caenorhabditis elegans and further evaluated the evolution dynamics with a computational model. Large population size was critical for rapid ivermectin resistance evolution in vitro and in silico. Male nematodes were favored during resistance evolution, indicating a selective advantage of sexual recombination under drug pressure in vitro. Ivermectin resistance evolution led to the expected emergence of cross-resistance to the structurally related anthelmintic moxidectin but unexpectedly also to the structurally unrelated anthelmintic emodepside that has an entirely different mode of action. In contrast, albendazole, levamisole, and monepantel efficacy were not influenced by the evolution of Ivermectin resistance. We conclude that combining computational modeling with in vitro evolution experiments to test specific aspects of evolution directly represents a promising approach to guide the development of novel treatment strategies to anticipate and mitigate resistance evolution in parasitic nematodes.

evolutionary biology↗

bioRxiv2024

Investigating the consequences of the mating system for drug resistance evolution in C. elegans

The rise of anthelmintic-resistant strains in livestock threatens both animal and human health. Understanding the factors influencing anthelmintic resistance is crucial to mitigate the threat posed by these parasites. Due to difficulties in studying parasitic worms in the laboratory, the non-parasitic nematode Caenorhabditis elegans is used as a model organism to investigate anthelmintic resistance evolution. However, the suitability of this free-living nematode as a model for parasitic worms is debatable due to its rare androdioecious reproductive system, raising questions about the generalizability of findings from evolutionary experiments in C. elegans to other species. In this study, we developed a polygenic, population genetic model combined with pharmacodynamic approaches to investigate the effects of reproductive strategy and other aspects, such as dominance, mutational effects, the number of loci, and population size, on determining the dynamics and outcome of evolutionary processes. We found that androdioecious populations showed both rapid initial adaptation typical for hermaphrodites and tolerance to high drug concentrations observed in dioecious populations. They also exhibited the highest diversity and shortest time for the fixation of the beneficial allele. These results suggest that androdioecious populations can harness the advantages of both selfing and outcrossing, optimizing their reproductive strategy in response to drug selection.

evolutionary biology↗