Beta-Lactamase Variability in Enterobacteriaceae

Beta-lactamases constitute a diverse family of enzymes that underlie the most widespread mechanism of resistance to β-lactam antibiotics in Enterobacteriaceae. Continuous exposure to penicillins, cephalosporins and monobactams has driven the emergence of extended-spectrum β-lactamases (ESBLs), AmpC enzymes and carbapenemases, each distinguished by substrate profile and inhibitor susceptibility. Sequence variation—arising through point mutations, gene amplification or horizontal gene transfer of plasmid-borne determinants—modulates the active site architecture, altering affinity for oxyimino-cephalosporins and β-lactamase inhibitors. Structural and kinetic studies have revealed that single amino acid changes can simultaneously expand substrate hydrolysis and thwart inhibitor binding, while alterations in regulatory elements and plasmid copy number further amplify resistance levels. This variability complicates clinical treatment, undermines diagnostic assays and fuels global dissemination, underscoring the need for integrative surveillance, rational inhibitor design and stewardship strategies to preserve the efficacy of β-lactam therapies.

Research from Nature Portfolio

Recent studies have characterised a series of CTX-M variants recovered from non-clinical reservoirs, demonstrating that mutations such as I176F and N135D reshape the enzyme’s binding pocket without gross structural destabilisation, thereby sustaining mecillinam interaction while enhancing resistance to third-generation cephalosporins. Homology modelling and molecular docking have pinpointed altered polar contacts that underpin this adaptive shift. In parallel, high-throughput screening of a comprehensive AmpC mutant library has uncovered rare “escape” substitutions that circumvent the classic trade-off between β-lactam hydrolysis and inhibitor susceptibility. These escape mutants display enhanced growth in the presence of avibactam-β-lactam combinations, mapping an adaptive landscape that highlights drug-specific liabilities and informs the selection of inhibitor-antibiotic pairs less prone to evolutionary breakthrough.

Beta-Lactamase Variability in Enterobacteriaceae publication trend

The graph below shows the total number of articles in beta-lactamase variability in enterobacteriaceae across all publications each year (not limited to Nature Index journals).

Technical terms

Beta-lactamase: Enzyme produced by bacteria that hydrolyses the β-lactam ring of antibiotics, inactivating them.

Extended-spectrum β-lactamase (ESBL): A subgroup of β-lactamases capable of hydrolysing penicillins and third-generation cephalosporins but usually inhibited by clavulanic acid.

AmpC β-lactamase: Class C β-lactamase that confers resistance to cephamycins and many cephalosporins and is typically not inhibited by clavulanic acid.

Oxyimino-cephalosporin: Cephalosporin derivative featuring an oxyimino side chain that enhances activity against β-lactamase–producing strains.

Plasmid: Circular, self-replicating DNA molecule that can carry and transfer antibiotic resistance genes between bacteria.

References

1. CTX-M-127 with I176F mutations found in bacteria isolates from Bangladeshi circulating banknotes. Scientific Reports (2024).
2. Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor. Nature Communications (2020).
3. Structural insights into the molecular mechanism of high-level ceftazidime–avibactam resistance conferred by CMY-185. mBio (2024).
4. A Novel CMY Variant Confers Transferable High-Level Resistance to Ceftazidime-Avibactam in Multidrug-Resistant Escherichia coli. Microbiology Spectrum (2023).