The Enterobacterales order represents Gram-negative bacteria that are found across nearly every environment. These organisms are ubiquitous, inhabiting soil, water, plants, and the intestinal tracts of humans and animals. This broad distribution means they function as harmless commensals, beneficial symbionts, and potent human pathogens. The medical importance of this order is immense, as they are responsible for a substantial portion of both community-acquired and hospital-acquired infections worldwide. Understanding the classification, genomic adaptability, and resistance mechanisms of Enterobacterales is fundamental to addressing the threat they pose to global public health.
Defining the Enterobacterales Order
The taxonomy of this bacterial group underwent reorganization in 2016, shifting the focus from the historical family Enterobacteriaceae to the order Enterobacterales. This change was driven by advanced molecular and phylogenetic analyses, which revealed the former family was too diverse and comprised several distinct evolutionary lineages. The order Enterobacterales now encompasses multiple families, including the emended Enterobacteriaceae, along with Morganellaceae, Yersiniaceae, and Hafniaceae, reflecting a more accurate genetic relationship among the members.
They are Gram-negative, rod-shaped bacteria. These organisms are classified as facultative anaerobes, meaning they can switch their metabolism to thrive in environments with or without oxygen. A shared biochemical trait is their ability to ferment glucose, often with the production of gas, and their inability to produce the enzyme oxidase.
Within this large order, several genera are implicated in human disease. The genus Escherichia, particularly E. coli, is the most frequently isolated organism in clinical laboratories, often residing in the gut as part of the normal flora. Other medically relevant genera include Klebsiella, Salmonella, Shigella, and Proteus, which can be found in the environment, in animal reservoirs, or as colonizers of the human gastrointestinal tract.
Genomic Drivers of Virulence
The ability of certain Enterobacterales species to cause severe disease is linked to specific genetic elements that enhance their pathogenic potential. These bacteria rapidly acquire and integrate foreign DNA that encodes for virulence factors. A primary mechanism for this acquisition is through the incorporation of specialized DNA segments known as pathogenicity islands (PAIs).
Pathogenicity islands are large clusters of genes acquired by the bacterium through horizontal gene transfer. PAIs encode the genetic instructions for major virulence factors, which allow the bacteria to colonize, evade host defenses, and cause tissue damage.
Specific virulence factors encoded on these islands include toxins and adhesins. All Gram-negative bacteria, including Enterobacterales, possess an outer membrane component called lipopolysaccharide (LPS). LPS acts as an endotoxin that can trigger a severe systemic inflammatory response, known as endotoxic shock, when released into the bloodstream. Many pathogens also utilize adherence mechanisms, such as fimbriae or pili, which are protein filaments that allow the bacterium to firmly attach to host cell surfaces.
The rapid spread of these virulence traits is facilitated by horizontal gene transfer (HGT). Mobile genetic elements like plasmids and bacteriophages (viruses that infect bacteria) act as vehicles, carrying PAI-associated genes from one bacterium to another. This genetic mobility allows non-pathogenic strains to quickly evolve into disease-causing variants through the acquisition of a single mobile element.
Specific Mechanisms of Antibiotic Resistance
The emergence of multidrug-resistant (MDR) Enterobacterales is driven by mechanisms for evading antimicrobial drugs. The most clinically concerning mechanism involves enzymatic inactivation, where the bacterium produces enzymes that chemically degrade the antibiotic molecule. This is prominent in the case of \(\beta\)-lactam antibiotics, such as penicillins and cephalosporins, which are rendered ineffective by \(\beta\)-lactamase enzymes.
Two classes of these enzymes are Extended-Spectrum \(\beta\)-Lactamases (ESBLs) and Carbapenemases. ESBLs break down a broad range of \(\beta\)-lactams, including third-generation cephalosporins, which are often first-line agents for serious infections. Carbapenemases inactivate carbapenems, which are frequently reserved as last-resort antibiotics.
Another primary defense mechanism is the use of efflux pumps, which are specialized protein complexes embedded in the bacterial membrane. These pumps actively transport antibiotic molecules out of the bacterial cell. Efflux systems often have broad substrate specificity, meaning a single pump can expel multiple, chemically distinct classes of antibiotics.
Bacteria also achieve resistance through target modification, changing the structure of the cellular component that the drug is designed to attack. For example, \(\beta\)-lactam antibiotics typically bind to and inactivate penicillin-binding proteins (PBPs) involved in cell wall synthesis; some resistant strains modify the PBP structure so the drug can no longer bind effectively. Changes in the outer membrane can also contribute to resistance by altering porins, which control the entry of substances, including antibiotics, into the cell.
The genes encoding these resistance traits, particularly those for ESBLs and Carbapenemases, are frequently located on mobile genetic elements like plasmids. This localization allows resistance to spread rapidly through horizontal gene transfer.
Spectrum of Clinical Infections and Management
Enterobacterales are responsible for a wide range of clinical diseases, often acting as opportunistic pathogens that take advantage of compromised hosts. The most common infections are those of the urinary tract (UTIs), with E. coli being the leading cause of both community-acquired and hospital-acquired cases. Other frequent presentations include pneumonia, typically seen in hospitalized patients, and intra-abdominal infections, such as those occurring after gastrointestinal surgery or perforation.
When these bacteria breach the body’s primary defenses, they can enter the bloodstream, causing bacteremia or sepsis, which carry a high risk of morbidity and mortality. Klebsiella, Enterobacter, and Serratia species are frequent causes of bloodstream infections, especially in intensive care settings. The reservoir for these organisms is diverse, ranging from the patient’s own gut flora to contaminated medical equipment or environmental surfaces within healthcare facilities, establishing them as major causes of healthcare-associated infections (HAIs).
The prevalence of multidrug resistance (MDR) among Enterobacterales has created significant therapeutic challenges for clinicians. When an infection is caused by an ESBL-producing strain, the traditional first-line antibiotics become ineffective, often necessitating the use of carbapenems. However, the emergence of carbapenem-resistant Enterobacterales (CRE) has complicated this approach, limiting treatment options severely.
For infections caused by CRE, treatment often relies on a limited arsenal of older or novel agents, sometimes used in combination therapy to maximize efficacy. Older drugs like colistin and fosfomycin are increasingly being repurposed, although their use is limited by potential toxicity and emerging resistance. Newer \(\beta\)-lactam/ \(\beta\)-lactamase inhibitor combinations, such as ceftazidime-avibactam or meropenem-vaborbactam, are now employed to treat specific carbapenemase-producing strains.
Effective management requires rapid diagnostic testing to identify the specific resistance mechanisms present. Surveillance of resistance patterns is also important for guiding empirical therapy before test results are available.