To fulfill their nutritional requirement for iron, bacteria utilize various iron sources which include the host proteins transferrin and lactoferrin, heme, and low molecular weight iron chelators termed siderophores. The iron sources are transported into the Gram-negative bacterial cell via specific uptake pathways which include an outer membrane receptor, a periplasmic binding protein (PBP), and an inner membrane ATP-binding cassette (ABC) transporter. Over the past two decades, structures for the proteins involved in bacterial iron uptake have not only been solved, but their functions have begun to be understood at the molecular level. However, the elucidation of the three dimensional structures of all components of the iron uptake pathways is currently limited. Despite the low sequence homology between different bacterial species, the available three-dimensional structures of homologous proteins are strikingly similar. Examination of the current three-dimensional structures of the outer membrane receptors, PBPs, and ABC transporters provides an overview of the structural biology of iron uptake in bacteria.

To maintain iron homeostasis within the cell, bacteria have evolved various types of iron acquisition systems. Ferric iron (Fe(3+)) is the dominant species in an oxygenated environment, while ferrous iron (Fe(2+)) is more abundant under anaerobic conditions or at low pH. For organisms that must combat oxygen limitation for their everyday survival, pathways for the uptake of ferrous iron are essential. Several bacterial ferrous iron transport systems have been described; however, only the Feo system appears to be widely distributed and is exclusively dedicated to the transport of iron. In recent years, many studies have explored the role of the FeoB and FeoA proteins in ferrous iron transport and their contribution toward bacterial virulence. The three-dimensional structures for the Feo proteins have recently been determined and provide insight into the molecular details of the transport system. A highly select group of bacteria also express the FeoC protein from the same operon. This review will provide a comprehensive look at the structural and functional aspects of the Feo system. In addition, bioinformatics analyses of the feo operon and the Feo proteins have been performed to complement our understanding of this ubiquitous bacterial uptake system, providing a new outlook for future studies.

Siderophores are biosynthetically produced and secreted by many bacteria, yeasts, fungi and plants, to scavenge for ferric iron (Fe(3+)). They are selective iron-chelators that have an extremely high affinity for binding this trivalent metal ion. The ferric ion is poorly soluble but it is the form of iron that is predominantly found in oxygenated environments. Siderophore uptake in bacteria has been extensively studied and over the last decade, detailed structural information for many of the proteins that are involved in their transport has become available. Specifically, numerous crystal structures for outer membrane siderophore transporters, as well as for soluble periplasmic siderophore-binding proteins, have been reported. Moreover, unique siderophore-binding proteins have recently been serendipitously discovered in humans, and the structures of some of their siderophore-complexes have been characterized. The binding pockets for different ferric-siderophores in these proteins have been described in great molecular detail. In addition to highlighting this structural information, in this review paper we will also briefly discuss the relevant chemical properties of iron, and provide a perspective on our current understanding of the human and bacterial iron uptake pathways. Potential clinical uses of siderophores will also be discussed. The emerging overall picture is that iron metabolism plays an extremely important role during bacterial infections. Because levels of free ferric iron in biological systems are always extremely low, there is serious competition for iron and for ferric-siderophores between pathogenic bacteria and the human or animal host.

Objectives: Use systematic review and meta-analytic methodology to estimate the pooled incidence, prevalence, and proportion of delirium cases for each delirium subtype (hypoactive, hyperactive, and mixed) in an adult ICU population. Data Sources: We conducted a search of the MEDLINE, EMBASE, CINAHL, SCOPUS, Web of Science, and PsycINFO databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards from database inception until October 22, 2017, with no restrictions. Study Selection: We included original research conducted in adults admitted to any medical, surgical, or speciality ICU that reported incidence or prevalence estimates of delirium according to delirium subtype. Data Extraction: Data were extracted on sample size, population demographics, condition information, and reported delirium estimates. Data Synthesis: Forty-eight studies (27,342 patients; 4,550 with delirium) with an overall pooled prevalence of 31% (95% CI, 24–41; I 2 = 99%) met inclusion criteria. The pooled incidence (n = 18 studies) of delirium subtypes were hyperactive (4% [95% CI, 2–6]; I 2 = 92%]), hypoactive (11% [95% CI, 8–17; I 2 = 97%]), and mixed (7% [95% CI, 4–11; I 2 = 97%]). The pooled prevalence (n = 31 studies) of delirium subtypes were hyperactive (4% [95% CI, 3–6; I 2 = 94%]), hypoactive (17% [95% CI, 13–22; I 2 = 97%]), and mixed (10% [95% CI, 6–16; I 2 = 99%]). The pooled prevalence of hypoactive delirium in study populations with a similarly high severity of illness or mechanically ventilated was higher (severity of illness: 29% [95% CI, 18–46%; I 2 = 95%], 100% mechanically ventilated: 35% [95% CI, 23–55%; I 2 = 93%]) compared with the pooled prevalence of hypoactive delirium. Conclusions: Despite significant heterogeneity between studies, these data show the majority of delirious ICU patients to have hypoactive delirium, a finding with potential monitoring, management, and prognostic implications. The prevalence of hypoactive delirium varies between-study populations and is higher in patients with greater severity of illness.

Bacteria are able to survive in low-iron environments by sequestering this metal ion from iron-containing proteins and other biomolecules such as transferrin, lactoferrin, heme, hemoglobin, or other heme-containing proteins. In addition, many bacteria secrete specific low molecular weight iron chelators termed siderophores. These iron sources are transported into the Gram-negative bacterial cell through an outer membrane receptor, a periplasmic binding protein (PBP), and an inner membrane ATP-binding cassette (ABC) transporter. In different strains the outer membrane receptors can bind and transport ferric siderophores, heme, or Fe3+ as well as vitamin B12, nickel complexes, and carbohydrates. The energy that is required for the active transport of these substrates through the outer membrane receptor is provided by the TonB/ExbB/ExbD complex, which is located in the cytoplasmic membrane. In this minireview, we will briefly examine the three-dimensional structure of TonB and the current models for the mechanism of TonB-dependent energy transduction. Additionally, the role of TonB in colicin transport will be discussed.