Bhattacharya Monolekha, Toth Marta, Antunes Nuno Tiago, Smith Clyde A, Vakulenko Sergei B
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California USA.
Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):760-71. doi: 10.1107/S1399004713033014. Epub 2014 Feb 22.
ADC-type class C β-lactamases comprise a large group of enzymes that are encoded by genes located on the chromosome of Acinetobacter baumannii, a causative agent of serious bacterial infections. Overexpression of these enzymes renders A. baumannii resistant to various β-lactam antibiotics and thus severely compromises the ability to treat infections caused by this deadly pathogen. Here, the high-resolution crystal structure of ADC-1, the first member of this clinically important family of antibiotic-resistant enzymes, is reported. Unlike the narrow-spectrum class C β-lactamases, ADC-1 is capable of producing resistance to the expanded-spectrum cephalosporins, rendering them inactive against A. baumannii. The extension of the substrate profile of the enzyme is likely to be the result of structural differences in the R2-loop, primarily the deletion of three residues and subsequent rearrangement of the A10a and A10b helices. These structural rearrangements result in the enlargement of the R2 pocket of ADC-1, allowing it to accommodate the bulky R2 substituents of the third-generation cephalosporins, thus enhancing the catalytic efficiency of the enzyme against these clinically important antibiotics.
ADC 型 C 类β-内酰胺酶包含一大类酶，它们由位于鲍曼不动杆菌染色体上的基因编码，鲍曼不动杆菌是严重细菌感染的病原体。这些酶的过表达使鲍曼不动杆菌对各种β-内酰胺抗生素产生耐药性，从而严重损害了治疗由这种致命病原体引起的感染的能力。在此，报道了 ADC-1 的高分辨率晶体结构，ADC-1 是这个临床上重要的抗生素耐药酶家族的首个成员。与窄谱 C 类β-内酰胺酶不同，ADC-1 能够对广谱头孢菌素产生耐药性，使它们对鲍曼不动杆菌失去活性。该酶底物谱的扩展可能是 R2 环结构差异的结果，主要是三个残基的缺失以及随后 A10a 和 A10b 螺旋的重排。这些结构重排导致 ADC-1 的 R2 口袋扩大，使其能够容纳第三代头孢菌素的庞大 R2 取代基，从而提高了该酶对这些临床上重要抗生素的催化效率。
