AmpC beta-lactamase

AmpC beta-lactamase
Name	AmpC beta-lactamase
EC number	3.5.2.6
CAS number	9073-60-3

AmpC beta-lactamase is a clinically significant enzyme belonging to the molecular class C of beta-lactamases, primarily produced by Gram-negative bacteria. It confers resistance to a broad spectrum of beta-lactam antibiotics, including many cephalosporins, and is notorious for its inducible expression, which can complicate antimicrobial therapy. The gene encoding this enzyme is often located on the chromosome of many Enterobacterales, such as Enterobacter cloacae and Citrobacter freundii, but can also be found on plasmids, facilitating wider dissemination.

Overview

AmpC beta-lactamases are a major group of antibiotic resistance enzymes that hydrolyze the beta-lactam ring, a core structural component of penicillins, cephalosporins, and related drugs. First identified in the 1970s, their name originates from their association with ampicillin resistance and their initial characterization in Escherichia coli strains. Unlike many other beta-lactamases, AmpC enzymes are not effectively inhibited by classic beta-lactamase inhibitors like clavulanic acid, which are commonly used in combinations such as amoxicillin-clavulanate. The World Health Organization lists certain bacteria producing these enzymes as critical priority pathogens due to the therapeutic challenges they pose.

Classification and genetics

AmpC beta-lactamases are classified under the Ambler molecular classification as class C beta-lactamases and within the Bush-Jacoby-Medeiros functional classification in Group 1. Genetically, the *ampC* gene is naturally chromosomal in many members of the Enterobacteriaceae family, including Serratia marcescens, Morganella morganii, and Providencia stuartii. Expression is typically tightly regulated by a complex system involving an inducer like certain beta-lactams and a repressor protein; however, mutations in regulatory genes can lead to constitutive expression and high-level resistance. Of grave concern is the mobilization of *ampC* genes onto plasmids, first reported in the late 1980s in Klebsiella pneumoniae, which allows for horizontal transfer to species like Escherichia coli and Salmonella that lack a chromosomal copy, spreading resistance rapidly.

Mechanism of action

The enzyme functions by catalyzing the hydrolysis of the amide bond within the essential beta-lactam ring of its substrate antibiotics. This chemical reaction involves a serine residue at the active site that forms a transient acyl-enzyme intermediate, rendering the antibiotic inactive. AmpC beta-lactamases exhibit a broad substrate profile, efficiently inactivating penicillins, cephalosporins (including cefoxitin and later-generation agents like ceftazidime), and are generally resistant to inhibition by clavulanic acid. Their activity can be induced by certain beta-lactams, such as cefoxitin or imipenem, which trigger a derepression of the *ampC* gene via a complex signal transduction pathway involving the AmpR regulator.

Clinical significance

AmpC beta-lactamase production is a formidable problem in clinical microbiology and hospital-acquired infections. Organisms with inducible or derepressed AmpC, such as Enterobacter cloacae and Pseudomonas aeruginosa, can cause outbreaks in settings like intensive care units. Infections include bacteremia, pneumonia, urinary tract infections, and intra-abdominal infections. The Centers for Disease Control and Prevention and the European Centre for Disease Prevention and Control monitor the spread of these resistant strains. A particular challenge is the phenomenon of selection during therapy, where exposure to certain broad-spectrum cephalosporins can select for mutants with stably derepressed, high-level AmpC production, leading to treatment failure.

Detection and testing

Accurate detection in the clinical laboratory is crucial for guiding therapy. Phenotypic tests include the cefoxitin disk test and the cefotetan disk test, as these inducers can help detect inducible AmpC. The boronic acid disk test is a common method, as compounds like phenylboronic acid act as inhibitors of AmpC and can be used in synergy tests with ceftazidime or cefotaxime. More definitive methods involve molecular techniques such as polymerase chain reaction for detecting specific *ampC* genes. Automated antimicrobial susceptibility testing systems, like those from bioMérieux or Beckman Coulter, often incorporate algorithms to flag potential AmpC producers, but confirmation may require specialized assays.

Treatment and resistance

Treating infections caused by AmpC-producing organisms is complex. Traditional third-generation cephalosporins are often ineffective. Recommended agents include fourth-generation cephalosporins like cefepime, which are stable against hydrolysis, and carbapenems such as meropenem or imipenem. However, the use of carbapenems is a risk factor for selecting carbapenem-resistant Enterobacteriaceae. Beta-lactamase inhibitors like avibactam and vaborbactam, used in combination with ceftazidime or meropenem respectively, can inhibit some plasmid-mediated AmpC enzymes. The rise of strains producing both AmpC and extended-spectrum beta-lactamases, or those with porin loss leading to carbapenem resistance, represents an escalating threat, driving research into novel antimicrobial agents and phage therapy.

Category:Enzymes Category:Antibiotic resistance