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The family Enterobacteriaceae belongs to the domain Bacteria, phylum Proteobacteria, class Gammaproteobacteria, and order Enterobacteriales (http://www.bacterio.net).

The Enterobacteriaceae are gram-negative, non–spore-forming, facultative anaerobes that are typically motile by means of peritrichous flagella, ferment glucose, reduce nitrate to nitrite, and produce catalase but not oxidase.

This chapter begins by discussing prototypical shared structural and pathogenic features of the family Enterobacteriaceae—mostly extrapolated from the study of Escherichia coli— followed by more detailed descriptions of particular pathogens.

The lower gastrointestinal tract is the predominant reservoir for Enterobacteriaceae, although these bacteria are also widely distributed in the environment. Furthermore, enterobacterial species frequently colonize the human genitourinary tract and oropharynx, especially in frequently hospitalized or immunosuppressed individuals.2–5

As with any gram-negative organism, members of the Enterobacteriaceae family feature a peptidoglycan cell wall in the periplasmic space between an inner and outer membrane (Fig. 218.1)

The Enterobacteriaceae are rod-shaped organisms, generally 1 to 3 μm in length and 0.5 μm in diameter, with a genome typically consisting of a single circular chromosome, although multiple plasmids may be present in the cytoplasm

The inner—or cystoplasmic—membrane is a phospholipid bilayer that maintains the proton motive force for energy storage and regulates the passage of molecules to and from the cytoplasm

The periplasmic space between the inner and outer membrane is an aqueous, oxidizing environment containing the peptidoglycan cell wall and a high concentration of proteins.16

The gram-negative cell wall is a thin layer of peptidoglycan—also called murein—composed of alternating N-acetylglucosamine and N-acetylmuramic acid amino sugars joined by β-1,4 linkages with a short peptide composed of l-alanine, d-glutamic acid, l-meso-diami- nopalmelic acid, and d-alanine attached to the carboxyl group of the muramic acid.17

The outer membrane is an asymmetrical lipid bilayer featuring a mostly phospholipid inner leaflet and an outer leaflet composed primarily of LPS.

The polarity of LPS in the outer leaflet prevents penetration of lipophilic molecules, including detergents, dyes, and hydrophobic antimicrobials.19

the repeating oligosaccharide attached to the LPS core is referred to as the O antigen, which is the basis for serogroup classification. Each species within the Enterobacteriaceae has multiple O-antigen types.

Other potential surface polysaccharides of the Enterobacteriaceae family include enterobacterial common antigen, colonic acid, and a wide variety of polysaccharide envelopes known as capsules

Many of the Enterobacteriaceae—including E. coli strains—feature a colonic acid layer, which resembles a subset of capsule types. True capsules are linked to either LPS or α-glycerol phosphate and are the basis of the K-antigen serotyping scheme.21

Some enterobacterial capsules can be quite luxuriant, imparting the highly mucoid colonial morphology to Klebsiella and Enterobacter species, for example.22

Flagella are flexible, rotating surface appendages that propel bacteria through liquid environments. Most members of the Enterobacteriaceae are motile by way of flagella, often emanating from all sides of the organism (Fig. 218.2A)

Even nonmotile Enterobacteriaceae sometime retain genes specific to flagellar expression and are then capable of motility under certain conditions.23

This diversity is represented in the H-antigen typing scheme, the third component of O:K:H serotyping.

Most of the Enterobacteriaceae produce thin nanofilaments extending from the bacterial surface called pili—also known as fimbriae—that mediate autoaggregation and adhesion to host cells.28

Furthermore, pili facilitate bacterial conjugation and are often encoded by plasmids— capable of harboring virulence and antimicrobial resistance genes—to mediate intercellular contact and genetic exchange.29

Although debate persists about what constitutes a true virulence factor, the principle of “molecular Koch’s postulate” provides a helpful conceptual framework for discussing the general features of the Enterobacteriaceae discussed here. This principle defines a virulence factor as causing disease whose severity is attenuated by mutation of the gene encoding this factor, which is then restored by reintroduction of the wild-type allele.44 As with all microbes, the common themes of pathogenicity include entry, establish- ment and multiplication, host defense avoidance, tissue damage, and exit.45

Many adhesins of the Enterobacteriaceae—including pili, outer membrane proteins, and even surface carbohydrates—have proven indispensable to infection.46 An organism may feature a number of adhesins at once or in sequence in response to environmental cues or as a result of random phase variation

Type 1 pili expression is subject to phase variation because of the invertible DNA element flanking the promoter of the fim operon, resulting in variable pili production depending on the organism’s environment.49 Furthermore, type 1 pili adhesion is enhanced by shear force such as the flow conditions of the genitourinary tract.50

Many members of the Enterobacteriaceae family produce toxins released into the environment or directed to host cells. Interesting to note, despite having proven activity in animal models or tissue culture cells, many enterobacterial toxins do not fully reproduce disease in the absence of the bacteria itself, which suggests that some toxins play only an ancillary or even an unknown role in pathogenesis.

Most of the Enterobacteriaceae also feature a type II secretion system (T2SS), a multiprotein complex spanning the periplasmic compartment. T2SSs can serve a variety of functions including extracellular secretion of toxins in addition to hydrolytic enzymes.67 For example, enterohemor- rhagic E. coli (EHEC) O157:H7 features a plasmid-encoded T2SS that secretes a metalloprotease capable of degrading the C1 esterase inhibitor involved in complement activation.68

The three major domains of LPS are the lipid A—or endotoxin—backbone, the core phosphorylated oligosaccharide, and the repeating oligosaccharide side chains.73

The repeating oligosaccharide—or O antigen—attached to the LPS core are highly variable and, again, are the basis of Kauffman O:K:H serotyping.

Genes responsible for O antigen synthesis are subject to interspecies lateral transfer, with E. coli alone featuring more than 170 different O-antigen serotypes.21,74

LPS, often bound to the host acute-phase protein LPS-binding protein (LBP), binds to CD14, where lipid A is recognized by the host pattern recognition receptor Toll-like receptor 4 (TLR4). The TLR4-MD2 complex activates NF-κB by the MyD88 pathway to initiate transcription of proinflammatory cytokines including tumor necrosis factor (TNF), chemokines, and major histocompatibility complex (MHC) receptors

This inflammatory immune response is responsible for septic shock but is also critical to host recovery. For example, mice deficient in TLR4 fail to control gram-negative infection, and TLR4 polymorphisms in humans are associated with more severe gram-negative infection.75,76

Enterobacterial capsules can help the organism survive in human serum by avoiding phagocytosis.77–79 Capsules from certain strains contribute particular pathogenic features—for example, the K1 capsule, implicated in neonatal meningitis–associated E. coli (NMEC), or the capsule responsible for the mucoid morphology of Klebsiella pneumoniae.80,81

Enterobacterial siderophores—such as enterobactin and aerobactin—are low-molecular-weight compounds with high affinity for iron that are synthesized, secreted, and recaptured by the organism.84–86

Virtually all organisms require iron as a metal cofactor for critical enzymatic processes. Many enterobacterial pathogens have developed highly efficient iron scavenger systems to compete with host iron-binding proteins, controlled by the ubiquitous transcription factor ferric uptake regular (Fur).82,83