Microbiology and Immunology

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Browsing Microbiology and Immunology by Author "Adams, F.G."

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    ItemOpen Access
    The membrane composition defines the spatial organization and function of a major Acinetobacter baumannii drug efflux system
    (American Society for Microbiology, 2021) Zang, M.; MacDermott-Opeskin, H.; Adams, F.G.; Naidu, V.; Waters, J.K.; Carey, A.B.; Ashenden, A.; McLean, K.T.; Brazel, E.B.; Jiang, J.-H.; Panizza, A.; Trappetti, C.; Paton, J.C.; Peleg, A.Y.; Köper, I.; Paulsen, I.T.; Hassan, K.A.; O'Mara, M.L.; Eijkelkamp, B.A.; Bonomo, R.A.
    Acinetobacter baumannii is one of the world’s most problematic nosocomial pathogens. The combination of its intrinsic resistance and ability to acquire resistance markers allow this organism to adjust to antibiotic treatment. Despite being the primary barrier against antibiotic stress, our understanding of the A. baumannii membrane composition and its impact on resistance remains limited. In this study, we explored how the incorporation of host-derived polyunsaturated fatty acids (PUFAs) is associated with increased antibiotic susceptibility. Functional analyses of primary A. baumannii efflux systems indicated that AdeB-mediated antibiotic resistance was impacted by PUFA treatment. Molecular dynamics simulations of AdeB identified a specific morphological disruption of AdeB when positioned in the PUFA-enriched membrane. Collectively, we have shown that PUFAs can impact antibiotic efficacy via a vital relationship with antibiotic efflux pumps. Furthermore, this work has revealed that A. baumannii’s unconditional desire for fatty acids may present a possible weakness in its multidrug resistance capacity. Importance: 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. Due to their relatively high abundance at the host-pathogen interface, PUFAs and other fatty acid species not commonly synthesized by A. baumannii may be actively acquired by A. baumannii during infection and change the biophysical properties of the membrane beyond that studied in standard laboratory culturing media. Our work illustrates how the membrane phospholipid composition impacts membrane protein function, which includes an important multidrug efflux system in extensively-drug-resistant A. baumannii. This work emphasizes the need to consider including host-derived fatty acids in in vitro analyses of A. baumannii. On a broader scope, this study presents new findings on the potential health benefits of PUFA in individuals at risk of contracting A. baumannii infections or those undergoing antibiotic treatment.
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    The molecular basis of Acinetobacter baumannii cadmium toxicity and resistance
    (American Society for Microbiology, 2021) Alquethamy, S.F.; Adams, F.G.; Maharjan, R.; Delgado, N.N.; Zang, M.; Ganio, K.; Paton, J.C.; Hassan, K.A.; Paulsen, I.T.; McDevitt, C.A.; Cain, A.K.; Eijkelkamp, B.A.; Kelly, R.M.
    Acinetobacter species are ubiquitous Gram-negative bacteria that can be found in water, soil, and as commensals of the human skin. The successful inhabitation of Acinetobacter species in diverse environments is primarily attributable to the expression of an arsenal of stress resistance determinants, which includes an extensive repertoire of metal ion efflux systems. Metal ion homeostasis in the hospital pathogen Acinetobacter baumannii contributes to pathogenesis, however, insights into its metal ion transporters for environmental persistence are lacking. Here, we studied the impact of cadmium stress on A. baumannii. Our functional genomics and independent mutant analyses revealed a primary role for CzcE, a member of the cation diffusion facilitator (CDF) superfamily, in resisting cadmium stress. We also show that the CzcCBA heavy metal efflux system contributes to cadmium efflux. Collectively, these systems provide A. baumannii with a comprehensive cadmium translocation pathway from the cytoplasm to the periplasm and subsequently the extracellular space. Furthermore, analysis of the A. baumannii metallome under cadmium stress showed zinc depletion, as well as copper enrichment, which are likely to influence cellular fitness. Overall, this work provides new knowledge on the role of a broad arsenal of membrane transporters in A. baumannii metal ion homeostasis. IMPORTANCE Cadmium toxicity is a widespread problem, yet the interaction of this heavy metal with biological systems is poorly understood. Some microbes have evolved traits to proactively counteract cadmium toxicity, including Acinetobacter baumannii, which is notorious for persisting in harsh environments. Here we show that A. baumannii utilises a dedicated cadmium efflux protein in concert with a system that is primarily attuned to zinc efflux to efficiently overcome cadmium stress. The molecular characterization of A. baumannii under cadmium stress revealed how active cadmium efflux plays a key role in preventing the dysregulation of bacterial metal ion homeostasis, which appeared to be a primary means by which cadmium exerts toxicity upon the bacterium.
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    The role of zinc efflux during Acinetobacter baumannii infection
    (American Chemical Society, 2020) Alquethamy, S.; Adams, F.G.; Naidu, V.; Khorvash, M.; Pederick, V.G.; Zang, M.; Paton, J.C.; Paulsen, I.T.; Hassan, K.; Cain, A.K.; McDevitt, C.A.; Eijkelkamp, B.A.
    Acinetobacter baumannii is a highly ubiquitous Gram-negative bacterium, that is associated with significant disease in immunocompromised individuals. The success of A. baumannii is partly attributable to its high level of antibiotic resistance. Further, A. baumannii expresses a broad arsenal of putative zinc efflux systems that are likely to aid environmental persistence and host colonisation, but detailed insights into how the bacterium deals with toxic concentrations of zinc is lacking. In this study we present the transcriptomic responses of A. baumannii to toxic zinc concentrations. Subsequent mutant analyses revealed a primary role for the resistance-nodulation-cell division heavy metal efflux system CzcCBA, and the cation diffusion facilitator transporter CzcD in zinc resistance. To examine the role of zinc at the host-pathogen interface we utilised a murine model of zinc deficiency and challenge with wild-type and czcA mutant cells, which identified highly site-specific roles for zinc during A. baumannii infection. Overall, we provide novel insight into the key zinc resistance mechanisms of A. baumannii and outline the role these systems play in enabling the bacterium to survive in diverse environments.
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    ItemOpen Access
    To make or take: bacterial lipid homeostasis during Infection
    (American Society for Microbiology, 2021) Adams, F.G.; Trappetti, C.; Waters, J.K.; Zang, M.; Brazel, E.B.; Paton, J.C.; Snel, M.F.; Eijkelkamp, B.A.; Bonomo, R.A.
    Bacterial fatty acids are critical components of the cellular membrane. A shift in environmental conditions or in the bacterium’s lifestyle may result in the requirement for a distinct pool of fatty acids with unique biophysical properties. This can be achieved by the modification of existing fatty acids or via de novo synthesis. Furthermore, bacteria have evolved efficient means to acquire these energy-rich molecules from their environment. However, the balance between de novo fatty acid synthesis and exogenous acquisition during pathogenesis is poorly understood. Here, we studied the mouse fatty acid landscape prior to and after infection with Acinetobacter baumannii, a Gram-negative, opportunistic human pathogen. The lipid fluxes observed following infection revealed fatty acid- and niche-specific changes. Lipidomic profiling of A. baumannii isolated from the pleural cavity of mice identified novel A. baumannii membrane phospholipid species and an overall increased abundance of unsaturated fatty acid species. Importantly, we found that A. baumannii relies largely upon fatty acid acquisition in all but one of the studied niches, the blood, where the pathogen biosynthesizes its own fatty acids. This work is the first to reveal the significance of balancing the making and taking of fatty acids in a Gram-negative bacterium during infection, which provides new insights into the validity of targeting fatty acid synthesis as a treatment strategy.