Nutrient Limitation Magnifies Fitness Costs of Antimalarial Drug Resistance Mutations.
Antimicrob Agents Chemother
; 66(5): e0152921, 2022 05 17.
Article
en En
| MEDLINE
| ID: mdl-35465723
Drug resistance mutations tend to disrupt key physiological processes and frequently carry fitness costs, which are a central determinant of the rate of spread of these mutations in natural populations. Head-to-head competition assays provide a standard approach to measuring fitness for malaria parasites. These assays typically use a standardized culture medium containing RPMI 1640, which has a 1.4- to 5.5-fold higher concentration of amino acids than human blood. In this rich medium, we predict that fitness costs will be underestimated because resource competition is weak. We tested this prediction using an artemisinin-sensitive parasite edited to contain kelch-C580Y or R561H mutations conferring resistance to artemisinin or synonymous control mutations. We examined the impact of these single amino acid mutations on fitness, using replicated head-to-head competition experiments conducted in media containing (i) normal RPMI, (ii) modified RPMI with reduced amino acid concentration, (iii) RPMI containing only isoleucine, or (iv) 3-fold diluted RPMI. We found a significant 1.3- to 1.4-fold increase in fitness costs measured in modified and isoleucine-only media relative to normal media, while fitness costs were 2.5-fold higher in diluted media. We conclude that fitness costs are strongly affected by media composition and will be significantly underestimated in normal RPMI. Several components differed between media, including pABA and sodium bicarbonate concentrations, so we cannot directly determine which is responsible. Elevated fitness costs in nature will limit spread of artemisinin (ART) resistance but will also promote evolution of compensatory mutations that restore fitness and can be exploited to maximize selection in laboratory experiments.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Malaria Falciparum
/
Artemisininas
/
Antagonistas del Ácido Fólico
/
Antimaláricos
Tipo de estudio:
Health_economic_evaluation
Límite:
Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos