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.
- Stewart, N. K., Smith, C. A., Antunes, N. T., Toth, M., Vakulenko, S. B. "Role of the hydrophobic bridge in the carbapenemase activity of class D -lactamases" 2019 Antimicrobial Agents and Chemotherapy, 63 (2), e02191-18. DOI:10.1128/AAC.02191-18.
- Liu, R., Miller, P. A., Vakulenko, S. B., Stewart, N. K., Boggess, W. C., Miller, M. J. "A Synthetic Dual Drug Sideromycin Induces Gram-Negative Bacteria to Commit Suicide with a Gram-Positive Antibiotic" 2018 Journal of Medicinal Chemistry, 61 (9), pp. 3845-3854. DOI:10.1021/acs.jmedchem.8b00218.
- Toth, M., Stewart, N. K., Smith, C., Vakulenko, S. B. "Intrinsic Class D ß-Lactamases of Clostridium difficile" 2018 mBio, 9 (6), DOI:10.1128/mBio.01803-18.
- Smith, C. A., Bhattacharya, M., Toth, M., Stewart, N. K., Vakulenko, S. B. "Aminoglycoside resistance profile and structural architecture of the aminoglycoside acetyltransferase AAC(6’)-Im" 2017 Microbial Cell, 4 (12), pp. 402-410. DOI:10.15698/mic2017.12.602.
- Toth, M., Smith, C. A., Antunes, N. T., Stewart, N. K., Maltz, L., Vakulenko, S. B. "The role of conserved surface hydrophobic residues in the carbapenemase activity of the class D ß-lactamases" 2017 Acta Crystallographica Section D: Structural Biology, 73 (8), pp. 692-701. DOI:10.1107/S2059798317008671.
- Toth, M., Antunes, N. T., Stewart, N. K., Frase, H., Bhattacharya, M., Smith, C. A., Vakulenko, S. B. "Class D ß-lactamases do exist in Gram-positive bacteria" 2016 Nature Chemical Biology, 12 (1), pp. 9-14. DOI:10.1038/nchembio.1950.