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Department of Medicine

Department of Medicine

   Division of Infectious Diseases

Research


Culyba Laboratory


Culyba Laboratory

Culyba's lab positions to make a significant impact through understanding the mechanisms driving the evolution of antibiotic resistance and discovering novel approaches to therapy. With expertise in the complementary areas of structural biology and biochemistry of DNA binding proteins, chemical biology of DNA and specialized DNA recombination enzymes, laboratory and clinical microbiology, the diagnosis and treatment of infections due to MDROs, and the drug discovery process within the pharmaceutical industry. Genetic diversity within bacterial populations is the driving force behind the evolution of antibiotic resistance in patients and is governed by the processes of mutation and horizontal gene transfer. Our research focuses on bacterial stress response pathways, which bacteria use to sense environmental cues in order to modulate the enzymes, which control these mutation and horizontal gene transfer processes. Culyba's proposed research and training plan builds off of strong foundation in these areas and will give additional skills required to make a positive and lasting impact on human health and disease.

Contributions to Science

Role of the poxvirus Holliday junction resolving enzyme in DNA replication. Holliday junction {HJ) resolving enzymes are required for genome replication in all branches of li fe and function to specifically cleave DNA 4-way junctions that arise during DNA replication and recombination. Our work has drawn interesting parallels between DNA viruses of eukaryotes (poxvirus) and those of prokaryotes {phage) and launched further studies by prominent researchers in the field of recombination biology.

Catalysis and inhibition of poxvirus resolvase. Additionally, we developed and patented a novel high throughput assay for DNA branch endonuclease activity and, through a collaboration with Merck & Co., we identified potent small molecule inhibitors of poxvirus resolvase, which allowed us to infer the catalytic mechanism of the DNA hydrolysis reaction and show that the active site of poxvirus resolvase contains two-metal ions. These results established that the family of enzymes related to poxvirus resolvase also use the same general cata lytic mechanism as the structurally related retroviral integrase and bacteria l RNaseH enzymes.

Targeting evolution to combat antimicrobial resistance. Bacteria possess a remarkable ability to acquire genetic resistance to antibiotics. This is accomplished through their ability to tolerate environmental stress by executing genetic tolerance programs called stress-response pathways and also through their ability to generate tremendous amounts of genetic diversity within their genomes through the processes of mutation and horizontal gene transfer.