The Response of Acinetobacter baumannii to Zinc Starvation

Nairn, Brittany L.; Lonergan, Zachery R.; Wang, Jiefei; Braymer, Joseph J.; Zhang, Yaofang; Calcutt, M. Wade; Lisher, John P.; Gilston, Benjamin A.; Chazin, Walter J.; Crécy‐Lagard, Valérie de; Giedroc, David P.; Skaar, Eric P.

doi:10.1016/j.chom.2016.05.007

Cited by 121 publications

(179 citation statements)

References 39 publications

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“…Multiple studies conducted by prominent laboratories have demonstrated that iron or zinc limitation can suppress Acinetobacter growth and that the organisms have multiple iron and zinc acquisition mechanisms, including catechol production, production of very high-affinity siderophores (e.g., acinetobactin) and companion siderophore uptake receptor and energetic mechanisms, and heme utilization (82,121,(308)(309)(310)(311)(312)(313)(314)(315)(316)(317)(318)(319)(320). Small-molecule iron chelators have in vitro activity at killing Acinetobacter during log growth (318).…”

Section: Trace Metal Sequestrationmentioning

confidence: 99%

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

et al. 2017

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SUMMARY Acinetobacter is a complex genus, and historically, there has been confusion about the existence of multiple species. The species commonly cause nosocomial infections, predominantly aspiration pneumonia and catheter-associated bacteremia, but can also cause soft tissue and urinary tract infections. Community-acquired infections by Acinetobacter spp. are increasingly reported. Transmission of Acinetobacter and subsequent disease is facilitated by the organism's environmental tenacity, resistance to desiccation, and evasion of host immunity. The virulence properties demonstrated by Acinetobacter spp. primarily stem from evasion of rapid clearance by the innate immune system, effectively enabling high bacterial density that triggers lipopolysaccharide (LPS)–Toll-like receptor 4 (TLR4)-mediated sepsis. Capsular polysaccharide is a critical virulence factor that enables immune evasion, while LPS triggers septic shock. However, the primary driver of clinical outcome is antibiotic resistance. Administration of initially effective therapy is key to improving survival, reducing 30-day mortality threefold. Regrettably, due to the high frequency of this organism having an extreme drug resistance (XDR) phenotype, early initiation of effective therapy is a major clinical challenge. Given its high rate of antibiotic resistance and abysmal outcomes (up to 70% mortality rate from infections caused by XDR strains in some case series), new preventative and therapeutic options for Acinetobacter spp. are desperately needed.

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Section: Trace Metal Sequestrationmentioning

confidence: 99%

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

et al. 2017

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“…More recently, other transporters have been shown to function in Zn uptake in S. enterica and Vibrio cholera (40,41). As discussed above, host strategies to limit bacterial infection exploit both zinc toxicity, perhaps best understood for intracellular niches (3,42), and severe zinc limitation (starvation) (43).…”

Section: Zinc Efflux and Acquisitionmentioning

confidence: 99%

“…The metal-free metallophore is proposed to be exported through CntE, a major facilitator superfamily (MFS) transporter, and then imported as the metallated complex via a specific ABC transporter, CntABCDF. B, model of how histidine uptake and catabolism impact the labile histidine-Zn pool in A. baumannii under conditions of host-mediated Zn starvation (43). His is proposed to be taken up as His 2 -Zn complex through HutT.…”

Section: Zinc Uptakementioning

confidence: 99%

“…ZigA is a Zn II -activated GTPase that may directly activate the Zn-stimulated metalloenzyme HutH (histidine ammonia lyase), which converts L-His to trans-urocanic acid (UA) and ultimately glutamate (Glu) via the sequential activities of HutUIG, all encoded by the hut (histidine utilization) operon. Urocanic acid (43) and glutamate have lower affinities for Zn than histidine, thus potentially mobilizing Zn from the labile or rapidly exchanging pool for use in Zn-requiring processes. C, schematic model of bacillithiol (BSH) biosynthesis (99) and known role of bacillithiol in buffering cytoplasmic Zn (94).…”

Section: Zinc Uptakementioning

confidence: 99%

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Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface

Capdevila

Wang

Giedroc

2016

Journal of Biological Chemistry

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147

139

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Among the biologically required first row, late d-block metals from Mn II to Zn II , the catalytic and structural reach of Zn II ensures that this essential micronutrient touches nearly every major metabolic process or pathway in the cell. Zn is also toxic in excess, primarily because it is a highly competitive divalent metal and will displace more weakly bound transition metals in the active sites of metalloenzymes if left unregulated. The vertebrate innate immune system uses several strategies to exploit this "Achilles heel" of microbial physiology, but bacterial evolution has responded in kind. This review highlights recent insights into transcriptional, transport, and trafficking mechanisms that pathogens use to "win the fight" over zinc and thrive in an otherwise hostile environment.

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“…We also amplified the isolated fepA gene using the same strategy. Following digestion, we ligated these two PCR products into pWH1266 or p2682pro (81) to make pAbafepA and p2682proAbafepA, respectively. For each construct, we confirmed the sequences of the promoter, terminator, and structural gene (McLab, San Francisco, CA).…”

Section: Methodsmentioning

confidence: 99%

Fluorescence High-Throughput Screening for Inhibitors of TonB Action

et al. 2017

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Gram-negative bacteria acquire ferric siderophores through TonBdependent outer membrane transporters (TBDT). By fluorescence spectroscopic hghthroughput screening (FLHTS), we identified inhibitors of TonB-dependent ferric enterobactin (FeEnt) uptake through Escherichia coli FepA (EcoFepA). Among 165 inhibitors found in a primary screen of 17,441 compounds, we evaluated 20 in secondary tests: TonB-dependent ferric siderophore uptake and colicin killing and proton motive force-dependent lactose transport. Six of 20 primary hits inhibited TonBdependent activity in all tests. Comparison of their effects on [ 59 Fe]Ent and [ 14 C]lactose accumulation suggested several as proton ionophores, but two chemicals, ebselen and ST0082990, are likely not proton ionophores and may inhibit TonBExbBD. The facility of FLHTS against E. coli led us to adapt it to Acinetobacter baumannii. We identified its FepA ortholog (AbaFepA), deleted and cloned its structural gene, genetically engineered 8 Cys substitutions in its surface loops, labeled them with fluorescein, and made fluorescence spectroscopic observations of FeEnt uptake in A. baumannii. Several Cys substitutions in AbaFepA (S279C, T562C, and S665C) were readily fluoresceinated and then suitable as sensors of FeEnt transport. As in E. coli, the test monitored TonB-dependent FeEnt uptake by AbaFepA. In microtiter format with A. baumannii, FLHTS produced Z= factors 0.6 to 0.8. These data validated the FLHTS strategy against even distantly related Gram-negative bacterial pathogens. Overall, it discovered agents that block TonB-dependent transport and showed the potential to find compounds that act against Gram-negative CRE (carbapenemresistant Enterobacteriaceae)/ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Our results suggest that hundreds of such chemicals may exist in larger compound libraries.IMPORTANCE Antibiotic resistance in Gram-negative bacteria has spurred efforts to find novel compounds against new targets. The CRE/ESKAPE pathogens are resistant bacteria that include Acinetobacter baumannii, a common cause of ventilator-associated pneumonia and sepsis. We performed fluorescence high-throughput screening (FLHTS) against Escherichia coli to find inhibitors of TonB-dependent iron transport, tested them against A. baumannii, and then adapted the FLHTS technology to allow direct screening against A. baumannii. This methodology is expandable to other drugresistant Gram-negative pathogens. Compounds that block TonB action may interfere with iron acquisition from eukaryotic hosts and thereby constitute bacteriostatic antibiotics that prevent microbial colonization of human and animals. The FLHTS method may identify both species-specific and broad-spectrum agents against Gram-negative bacteria.

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The Response of Acinetobacter baumannii to Zinc Starvation

Cited by 121 publications

References 39 publications

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of Challenges

Bacterial Strategies to Maintain Zinc Metallostasis at the Host-Pathogen Interface

Fluorescence High-Throughput Screening for Inhibitors of TonB Action

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