A Trade-off between the Fitness Cost of Functional Integrases and Long-term Stability of Integrons

Abstract

Horizontal gene transfer (HGT) plays a major role in bacterial microevolution as evident from the rapid emergence and spread of antimicrobial drug resistance. Few studies have however addressed the population dynamics of newly imported genetic elements after HGT. Here, we show that newly acquired class-1 integrons from Salmonella enterica serovar Typhimurium and Acinetobacter baumannii, free of associated transposable elements, strongly reduce host fitness in Acinetobacter baylyi. Insertional inactivation of the integron intI1 restored fitness, demonstrating that the observed fitness costs were due to the presence of an active integrase. The biological cost of harboring class-1 integrons was rapidly reduced during serial transfers due to intI1 frameshift mutations leading to inactivated integrases. We use a mathematical model to explore the conditions where integrons with functional integrases are maintained and conclude that environmental fluctuations and episodic selection is necessary for the maintenance of functional integrases. Taken together, the presented data suggest a trade-off between the ability to capture gene cassettes and long-term stability of integrons and provide an explanation for the frequent observation of inactive integron-integrases in bacterial populations.

Author Summary

Horizontal acquisition of mobile and mobilizable genetic elements plays a major role in the development of antimicrobial drug resistance in bacteria. Despite their causal role in drug treatment failure, there is only limited understanding of how horizontal acquisitions of these elements affect bacterial fitness. A prominent group of such genetic elements are the integrons. These genetic elements harbor an integrase-gene that allows the integron to respond to environmental changes by capture and excision of gene cassettes. Here, we have experimentally determined if horizontal acquisition of an integron affect host fitness. The data demonstrate that the initial costs are substantial. However, inactivation of the integrase gene occurred rapidly by spontaneous mutation alleviating the detrimental effect of the integron on bacterial fitness. The same fitness restoring effects was also shown by targeted inactivation of the integrase gene. The inactivation results in a negative trade-off between host adaptation and loss of the ability to capture new gene cassettes. Importantly, our results explain the frequent observation of inactive integrase genes in integrons found in bacteria of different origins. Finally, we use mathematical modeling to determine the conditions necessary for maintaining functional integrases.