Dr. Victor Nizet: Drug Discovery

Research Summary: New Anti-Infective Therapies

Dr. Nizet’s laboratory interests lie in understanding the fundamental mechanisms of bacterial pathogenesis and the innate immune system, with a special focus on human streptococcal and staphylococcal infections. Using a molecular genetic approach, the laboratory seeks to discover and characterize bacterial virulence determinants involved in cytotoxicity, adherence, invasion, inflammation, molecular mimicry and resistance to immunologic clearance. In companion studies, we investigate the contribution of host factors such as antimicrobial peptides, leukocyte surface receptors, signal transduction pathways, and transcription factors in defense against invasive bacterial infection.

We have shown that the basic information gained through this platform can lead to novel treatment strategies for infectious diseases, involving targeted neutralization of bacterial virulence phenotypes and pharmacologic augmentation of host innate immune function. Additional research examines marine natural product resources for antibiotic activities against drug-resistant pathogens and novel vaccine approaches to prevent infection by leading Gram- positive bacterial pathogens.

Academic Achievements

Education: B.A. in Biology (1984) Reed College; M.D. (1989) Stanford University, Pediatric Residency & Chief Residency (1993) Harvard University, Pediatric Infectious Diseases Fellowship (1997) University of Washington.

Awards and Honors: The 39th Malinckrodt Scholar (2002); ALA Career Investigator Award (2004); AHA Established Investigator Award (2004); American Society for Clinical Investigation (2006); E. Mead Johnson Award for Research in Pediatrics (2008).

Leadership Experience: Track Leader, Microbiology & Immunology, UCSD Biomedical Sciences Graduate Program (2005-now); Chief, Division of Pediatric Pharmacology & Drug Discovery UCSD (2006-).

Teaching

• Pathogens and Host Defense (BIOM 253)
• From the Molecule to the Organism (BIOM 200)
• Medical Microbiology (SOM 208)

Key Contributions to Pharmaceutical Sciences

• Discovered the genetic basis and virulence role of the group A and group B streptococcal β-hemolysins.
• Elucidated mechanisms of group B streptococcal and pneumococcal blood-brain barrier penetration
• Discovered the role of the Staphylococcus aureus pigment as a virulence factor and therapeutic target.
• Revealed HIF-1 as a master regulator of phagocyte function and drug target for boosting innate immunity.

Selected Recent Publications (from >150 peer-reviewed articles)

Nizet et al. (2007). Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J. Allergy Clin. Immunol. 120:13-22.

Walker et al. (2007). DNase-mediated resistance to neutrophil killing provides selection pressure for a genetic and phenotypic switch promoting invasive group A streptococcal infection Nat. Med. 13:981- 985.

Liu et al. (2008). A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319:1391-1394.

Carlin et al. (2009). Group B Streptococcus suppression of phagocyte functions by protein- mediated engagement of human Siglec 5. J Exp Med 206:1691-1699. (cover article)

Nizet et al. (2009). Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 9:609- 617. (cover article)

Potential Collaborative Programs with the Pharmaceutical Industry

• 15 years experience in clinical infectious diseases and basic microbiology and immunology research
• Broad array of molecular genetic, cellular, and in vivo laboratory approaches to understanding virulence mechanisms and therapeutic approaches to leading bacterial pathogens.
• Scientific founder of two biotechnology companies for novel infectious disease therapy