The Membrane Composition Defines the Spatial Organization and Function of a Major Acinetobacter baumannii Drug Efflux System

Abstract

Antimicrobial resistance is an emerging global health crisis. Consequently, we have a critical need to prolong our current arsenal of antibiotics, in addition to the development of novel treatment options.

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

“…In contrast to the minimal impact on resistance to macrolides, we showed that antimicrobial host fatty acids of both the omega-6 and omega-3 classes improved the efficacy of aminoglycosides in A. baumannii . This suggests that omega-6 PUFAs affect the structure and function of AdeABC, similar to findings described for DHA ( 18 ). Importantly, both PUFAs alleviated the antimicrobial activity of colistin, possibly through extracellular sequestration, which renders these cationic antimicrobial peptides too hydrophobic to readily pass the hydrophilic capsule and lipooligosaccharide barriers of the bacterium.…”

“…Despite their known interactions with lipids, our work showed that macrolide antibiotics retain similar anti- Acinetobacter activity in the presence of PUFAs. This may be a result of these molecules being substrates of both AdeABC and AdeIJK ( 13 , 30 ); although AdeABC efflux activity is reduced in the presence of PUFA ( 18 ), the transcriptional activation of adeIJK , as illustrated in this study, may counteract this. In contrast to the minimal impact on resistance to macrolides, we showed that antimicrobial host fatty acids of both the omega-6 and omega-3 classes improved the efficacy of aminoglycosides in A. baumannii .…”

“…Subsequent examination showed that the AdeR I27S mutation leads to increased DHA susceptibility, which could, in part, suggest that the upregulation of adeABC in response to antibiotic stress is unfavorable in the presence of host lipids. Our previous analysis indicated that the incorporation of DHA in the A. baumannii membrane has a profound impact on the structural integrity of AdeB, leading to impaired efflux activity and increased susceptibility to aminoglycosides ( 18 ). This adverse effect of DHA on AdeABC could be associated with a reduction in adeRS mutations, since there is no benefit to upregulating a functionally disrupted efflux system.…”

“…The RND efflux system AdeIJK has been found to contribute to phospholipid homeostasis, which provides indirect protection against DHA stress ( 19 ). In contrast, recent analyses have shown that DHA incorporation in the A. baumannii phospholipid membrane affects the structure and function of the AdeABC RND efflux system ( 18 ). Considering the ability of A. baumannii to adapt rapidly to clinical treatment during infection and the intricate interplay between lipid homeostasis and antimicrobial resistance, such as that mediated by RND pumps, we sought to determine the impact of PUFAs on the ability of A. baumannii to gain resistance.…”

“…Antimicrobial resistance is mostly studied in standard laboratory media, and the impact of host molecules is thus overlooked. Fatty acids are highly abundant in most host niches, they are nearly indiscriminately acquired by A. baumannii , and they can impact A. baumannii physiology ( 18 – 21 ). The nearly universal antimicrobial activity of the long-chain polyunsaturated fatty acids (PUFAs) (with ≥16 carbons and ≥2 double bonds) that belong to the omega-3 and omega-6 groups has been well established ( 19 , 22 ).…”