SEP 14, 2017 07:30 AM PDT
Keynote Presentation: A Mechanistic Approach to Overcoming Antibacterial Drug Resistance
Presented at the Microbiology & Immunology 2017 Virtual Event
CONTINUING EDUCATION (CME/CE/CEU) CREDITS: CME | P.A.C.E. CE | Florida CE
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Speakers:
  • Professor of Biochemistry, John Coniglio Chair in Biochemistry, Vanderbilt University School of Medicine
    Biography
      Neil Osheroff received a Bachelor's Degree in Chemistry from Hobart College in 1974 followed by a Ph.D. in Biochemistry and Molecular Biology from Northwestern University in 1979. His doctoral dissertation on the mechanism of action of cytochrome c was under the direction of Professor Emanuel Margoliash.

      Following his doctoral studies, Dr. Osheroff moved to the Stanford University School of Medicine in 1980, where he was a Helen Hay Whitney Foundation postdoctoral fellow with Dr. Douglas Brutlag in the Department of Biochemistry. In 1983, he moved to the Vanderbilt University School of Medicine as an Assistant Professor of Biochemistry and he has been on the faculty since that time. Dr. Osheroff currently holds Professorships in the Departments of Biochemistry and Medicine and was endowed with the John G. Coniglio Chair in Biochemistry in 2003. He has spent a combined 27 years on the editorial boards of The Journal of Biological Chemistry and Biochemistry and has authored over 240 publications.

      Dr. Osheroff's research focuses on topoisomerases, enzymes that remove knots and tangles from the genetic material and modulate torsional stress in DNA. In addition to their critical physiological roles, human type I and II topoisomerases are the targets for a number of widely used anticancer drugs. Furthermore, bacterial type II topoisomerases are the targets for quinolones, a drug class that includes some of the most frequently prescribed antibacterials in the world. The Osheroff laboratory has made seminal contributions to our understanding of how topoisomerases function and how anticancer drugs, natural products, and antibacterials interact with these enzymes and alter their catalytic functions.

      Beyond his research, Dr. Osheroff has a long-standing interest in mentoring and training young scientists and physicians. Twenty-seven Ph.D. students have graduated under his mentorship. Dr. Osheroff he has been a course director since 1990 and holds a number of educational leadership positions in the Vanderbilt University School of Medicine.

      Dr. Osheroff Chaired the NCI-I "Transition to Independence" study section from 2013-2016 and has held leadership positions in two international medical science educator organizations.

      Finally, Dr. Osheroff has received awards for mentoring, teaching, curricular design, educational service, and affirmative action and diversity. Over the past five years, he has been invited to present more than seventy scientific and educational talks at forty-six institutions/meetings in seventeen different countries.

    Abstract:

    Quinolones are one the most commonly prescribed classes of antibacterials in the world and are used to treat a broad variety of Gram-negative and Gram-positive bacterial infections in humans. However, because of the wide use (and overuse) of these drugs, the number of quinolone resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. 

    Quinolones target the bacterial type II topoisomerases, gyrase and topoisomerase IV. These enzymes regulate DNA under- and over-winding and remove knots and tangles from the genome. Gyrase and topoisomerase IV create transient double-stranded breaks in the genetic material in order to carry out their essential cellular functions. Quinolones take advantage of this enzyme-mediated DNA cleavage activity and kill cells by converting gyrase and topoisomerase IV, into toxic “nucleases” that fragment the bacterial chromosome.

    Quinolone resistance is most often associated with mutations at two highly conserved amino acid residues (a serine and an acidic residue) in gyrase and/or topoisomerase IV. Recent structural and biochemical studies have determined how these two residues facilitate drug-enzyme interactions. Quinolones contain a keto acid group that chelates a non-catalytic Mg2+ ion, which in turn is coordinated by four water molecules. Two of these water molecules are situated close enough to the serine and acidic residue to form hydrogen bonds. For clinically relevant quinolones, this “water-metal ion bridge” serves as the primary interaction between the drug and the bacterial type II topoisomerases.

    Dr. Osheroff’s talk will provide background on DNA topology and type II topoisomerases. It will go on to describe experiments that led to the discovery of the water-metal ion bridge and defined its role in mediating quinolone-enzyme interactions. The talk will describe how this knowledge has been used to design novel quinolones and quinolone-based drugs that overcome resistance. Finally, it will discuss recent experiments with novel naphthyridone-based drugs that alter gyrase-mediated DNA cleavage by a unique mechanism and retain their activity against quinolone-resistant mutant enzymes.


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