Professor Vakulenko received his M.D. in 1976 from the St. Petersburg I. I. Mechnikov State Medical Academy, Russia. He earned his Ph.D. in medicine in 1981 and D.Sc. in biology in 1991 from National Research Center of Antibiotics, Moscow, Russia. Dr. Vakulenko joined the Notre Dame faculty in 2003.
Currently, more than a hundred antibiotics belonging to a dozen chemically distinct classes are available for the treatment of various bacterial infections. Widespread and often uncontrolled use of these compounds in humans and in veterinary medicine has resulted in the selection of antibiotic-resistant pathogens, and this severely compromises the available therapeutic options. The Vakulenko laboratory is involved in studies of mechanisms of bacterial resistance to two major classes of antibiotics, β-lactams and aminoglycosides. β-lactams kill pathogens by inhibiting synthesis of the microbial cell wall, while aminoglycosides bind to the bacterial ribosome and interfere with protein synthesis. Resistance to β-lactam antibiotics in Gram-negative bacteria is mainly due to the production of β-lactamases, enzymes that hydrolyze these drugs and render them inactive. Bacterial resistance to aminoglycosides is largely the result of their enzymatic modification by three types of aminoglycoside-modifying enzymes, aminoglycoside acetyltransferases, -phosphotransferases and -nucleotidyltransferases. Modified antibiotics have diminished affinity for their target, bacterial ribosome, and thus are less active.
In this laboratory we perform microbiological, kinetic and structural characterization of clinically important β-lactamases and aminoglycoside-modifying enzymes to gain insights into their architecture and interaction with substrates. To better understand evolutionary pathways leading to antibiotic resistance, we conduct directed evolution of these enzymes to select for mutants with an extended-spectrum of activity, often to include some of the most valuable antibiotics such as expanded-spectrum cephalosporins and carbapenems. These studies aim to facilitate understanding of antibiotic resistance mechanisms and their evolution, to forecast the appearance of novel resistant mutants and to develop new strategies to counter such resistance.
1. Structural Basis for Carbapenemase Activity of the OXA-23 β-Lactamase from Acinetobacter baumannii. Smith CA, Antunes NT, Stewart NK, Toth M, Kumarasiri M, Chang M, Mobashery S, Vakulenko SB., Chem Biol. 2013 Sep 19; 20(9):1107-15. Link
2. A novel extended-spectrum β-lactamase, SGM-1, from an environmental isolate of Sphingobium sp. Lamoureaux T, Vakulenko V, Toth M, Frase H, Vakulenko SB. Antimicrob Agents Chemother. 2013 Aug; 57(8):3783-8. Link
3. Structural basis for progression toward the carbapenemase activity in the GES family of β-lactamases. Smith CA, Frase H, Toth M, Kumarasiri M, Wiafe K, Munoz J, Mobashery S, Vakulenko SB. J Am Chem Soc. 2012 Dec 5;134(48):19512-5. Link
4. Revisiting the nucleotide and aminoglycoside substrate specificity of the bifunctional aminoglycoside acetyltransferase(6')-Ie/aminoglycoside phosphotransferase(2'')-Ia enzyme. Frase H, Toth M, Vakulenko SB. J Biol Chem. 2012 Dec 21;287(52):43262-9. Link
5. Aminoglycoside 2''-phosphotransferase IIIa (APH(2'')-IIIa) prefers GTP over ATP: structural templates for nucleotide recognition in the bacterial aminoglycoside-2'' kinases. Smith CA, Toth M, Frase H, Byrnes LJ, Vakulenko SB. J Biol Chem. 2012 Apr 13;287(16):12893-903. Link