Sergei Vakulenko

Research Professor

340D Mccourtney Hall
Notre Dame, IN 46556
+1 574-631-2935

Research Areas

  • Biochemistry

Research Specialties

  • Life Processes
  • Medicine

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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.

Selected Publications

  • Stewart, N. K.; Toth, M.; Quan, P. J.; Beer, M.; Buynak, J. D.; Smith, C. A. and Vakulenko, S. B. "Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase" 2024 ACS Infectious Diseases, 10 (4), pp.1232-1249. DOI: 10.1021/acsinfecdis.3c00683.
  • Smith, C. A.; Stewart, N. K.; Toth, M.; Quan, P. J.; Buynak, J. D. and Vakulenko, S. B. "The C5α-Methyl-Substituted Carbapenem NA-1-157 Exhibits Potent Activity Against Klebsiella Spp. Isolates Producing OXA-48-Type Carbapenemases" 2023 ACS Infectious Diseases, 9 (5), pp.1123-1136. DOI: 10.1021/acsinfecdis.3c00059.
  • Toth, M.; Stewart, N. K.; Smith, C. A.; Lee, M. J. and Vakulenko, S. B. "The L,D-Transpeptidase Ldt(Ab) from Acinetobacter Baumannii is Poorly Inhibited by Carbapenems and has a Unique Structural Architecture" 2022 ACS Infectious Diseases, 8 (9), pp.1948-1961. DOI: 10.1021/acsinfecdis.2c00321.
  • Stewart, N. K.; Toth, M.; Alqurafi, M. A.; Chai, W. R.; Nguyen, T. Q.; Quan, P. J.; Lee, M. J.; Buynak, J. D.; Smith, C. A. and Vakulenko, S. B. "C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Acinetobacter Baumannii Carbapenemase OXA-23 by Impeding Deacylation" 2022 mBio, 13 (3), e00367-22. DOI: 10.1128/mbio.00367-22.
  • Toth, M.; Lee, M.; Stewart, N. K. and Vakulenko, S. B. "Effects of Inactivation of D,D-Transpeptidases of Acinetobacter Baumannii on Bacterial Growth and Susceptibility to Beta-Lactam Antibiotics" 2022 Antimicrobial Agents and Chemotherapy, 66 (1), e01729-21. DOI: 10.1128/AAC.01729-21.
  • Stewart, N. K.; Toth, M.; Stasyuk, A.; Vakulenko, S. B. and Smith, C. A. "In Crystallo Time-Resolved Interaction of the Clostridioides Difficile CDD-1 Enzyme with Avibactam Provides New Insights into the Catalytic Mechanism of Class D Beta-Lactamases" 2021 ACS Infectious Diseases, 7 (6), pp.1765-1776. DOI: 10.1021/acsinfecdis.1c00094.