Sergei Vakulenko

Sergei Vakulenko

Biography

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.

Research Interests

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.
 

Recent Publications

  • Stewart, N. K., Toth, M., Stasyuk, A., Lee, M., Smith, C. A., Vakulenko, S. B. "Inhibition of the Clostridioides difficile Class D β-Lactamase CDD-1 by Avibactam" 2021 ACS Infectious Diseases, 7 (5), pp. 1164-1176. DOI:10.1021/acsinfecdis.0c00714.
  • Stewart, N. K., Bhattacharya, M., Toth, M., Smith, C. A., Vakulenko, S. B. "A surface loop modulates activity of the Bacillus class D β-lactamases" 2020 Journal of Structural Biology, 211 (2), 107544. DOI:10.1016/j.jsb.2020.107544.
  • Smith, C. A., Stewart, N. K., Toth, M., Vakulenko, S. B. "Structural insights into the mechanism of carbapenemase activity of the OXA-48 β-lactamase" 2019 Antimicrobial Agents and Chemotherapy, 63 (10), e01202-19. DOI:10.1128/AAC.01202-19.
  • Smith, C. A., Toth, M., Stewart, N. K., Maltz, L., Vakulenko, S. B. "Structural basis for the diversity of the mechanism of nucleotide hydrolysis by the aminoglycoside-2′′-phosphotransferases Smith Clyde A." 2019 Acta Crystallographica Section D: Structural Biology, 75, pp. 1129-1137. DOI:10.1107/S2059798319015079.
  • 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.
  • Stewart, N. K., Smith, C. A., Toth, M., Stasyuk, A., Vakulenko, S. B. "The crystal structures of CDD-1, the intrinsic class D β-lactamase from the pathogenic Gram-positive bacterium Clostridioides difficile, and its complex with cefotaxime" 2019 Journal of Structural Biology, 208 (3), 107391. DOI:10.1016/j.jsb.2019.09.008.

Contact Information

  • Research Professor
  • Office: 340D McCourtney Hall
  • Phone: 574-631-2935
  • Send an email

Primary Research Areas

Research Specialties