Abstract

Antibiotic resistance in the pathogenic bacterial strain Acinetobacter baumannii has increased greatly in recent years, partially due to their production of specific β-lactamases: Acinetobacter-derived cephalosporinases (ADCs). As these bacteria propagate in the environment, small mutations in the amino acid sequences of ADCs have resulted in the development of new variants, such as ADC-219 and ADC-33. The only difference between these variants is one amino change from a glycine (ADC-33) to an aspartate (ADC-219). While the potential significance of this mutation was unknown, the specific location of the alteration is in a section of the enzyme that facilitates the binding of the antibiotic molecule. In our work, kinetic analyses demonstrated that ADC-219 had much lower ability to bind and inactivate larger cephalosporin antibiotics than ADC-33. Using X-ray crystallography, we are determining the molecular structure of ADC-219 in the absence and presence of an inhibitory molecule. Taken together, this combination of structural and functional studies of ADC-219 offers critical insights into how specific variants may affect antibiotic resistance.