The Impact of Omega-3 Fatty Acids on the Evolution of Acinetobacter baumannii Drug Resistance

Abstract

ABSTRACT The bacterial pathogen Acinetobacter baumannii has emerged as an urgent threat to health care systems. The prevalence of multidrug resistance in this critical human pathogen is closely associated with difficulties in its eradication from the hospital environment and its recalcitrance to treatment during infection. The development of resistance in A. baumannii is in part due to substantial plasticity of its genome, facilitating spontaneous genomic evolution. Many studies have investigated selective pressures imposed by antibiotics on genomic evolution, but the influence of high-abundance bioactive molecules at the host-pathogen interface on mutation and rates of evolution is poorly understood. Here, we studied the roles of host fatty acids in the gain in resistance to common antibiotics. We defined the impact of the polyunsaturated fatty acids arachidonic acid and docosahexaenoic acid on the development of resistance to erythromycin in A. baumannii strain AB5075_UW using a microevolutionary approach. We employed whole-genome sequencing and various phenotypic analyses to characterize microbe-lipid-antibiotic interactions. Cells exposed to erythromycin in the presence of the fatty acids displayed significantly lower rates of development of resistance to erythromycin and, importantly, tetracycline. Subsequent analyses defined diverse means by which host fatty acids influence the mutation rates. This work has highlighted the critical need to consider the roles of host fatty acids in A. baumannii physiology and antimicrobial resistance. Collectively, we have identified a novel means to curb the development of resistance in this critical human pathogen. IMPORTANCE The global distribution of multidrug resistance in A. baumannii has necessitated seeking not only alternative therapeutic approaches but also the means to limit the development of resistance in clinical settings. Highly abundant host bioactive compounds, such as polyunsaturated fatty acids, are readily acquired by A. baumannii during infection and have been illustrated to impact the bacterium’s membrane composition and antibiotic resistance. In this work, we show that in vitro supplementation with host polyunsaturated fatty acids reduces the rate at which A. baumannii gains resistance to erythromycin and tetracycline. Furthermore, we discover that the impact on resistance development is closely associated with the primary antimicrobial efflux systems of A. baumannii, which represent one of the major drivers of clinical resistance. Overall, this study emphasizes the potential of host macromolecules in novel approaches to circumvent the difficulties of multidrug resistance during A. baumannii treatment, with fatty acid supplements such as fish oil providing safe and cost-effective ways to enhance host tolerance to bacterial infections.

Keywords

• antimicrobial host lipids
• free fatty acids
• macrolides
• resistance evolution
• RND efflux
• AdeABC