Physician Image

Fred Krebs

Associate Professor

  • Department: Microbiology and Immunology
  • Research interests: Microbicide development, HIV-1 transmission, HIV-1 immunopathogenesis and neurogenesis
  • Education: Ph.D., 1996, Penn State College of Medicine, Hershey, PA
  • Research Staff: Shendra Miller Passic, M. S.
  • Graduate Students:Shawn Keogan and Karissa Lozenski
Research

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) has become an increasingly significant component of the worldwide spread of HIV-1 and the acquired immune deficiency syndrome (AIDS) pandemic.  Although safe sexual practices, including condom usage, can reduce the risk of HIV-1 transmission, cultural factors and gender inequality issues limit the consistent and effective use of condoms and other preventative measures. As a result, there is an urgent need for safe and effective approaches that can protect women from HIV-1 infection. To meet this need, increasing efforts have been directed toward the development of topical agents, collectively termed microbicides, that would be used within the female reproductive tract to prevent HIV-1 transmission.

The long-term interest of our research group has been the discovery and development of HIV-1 inhibitors to be used in safe and effective microbicides. Molecules that have been the focus of these efforts include the biguanide-based NB325, the carbohydrate-based HPMCT, and the co-polymer PSMA (all developed in collaboration with Novaflux Technologies, Inc., Princeton, NJ). These and other agents are evaluated using a wide range of experimental approaches used to establish range of activity, mechanism of action, activity in combination with other inhibitors, and in vivo safety. These and other investigational strategies are designed to significantly advance the pre-clinical development of microbicide compounds and lay a solid foundation for clinical trials of products that can be used to reduce or eliminate the risk of HIV-1 transmission during sexual intercourse.

Ongoing investigations are also focused on developing a greater understanding of the mechanisms that underlie HIV-1 heterosexual transmission. Areas of interest include (i) cervicovaginal epithelial damage and inflammation associated with single and multiple applications of topical microbicides, (ii) epithelial tissue repair mechanisms that may impact susceptibility to HIV-1 infection, and (iii) the effect of semen on HIV-1 transmission across cervicovaginal mucosal tissues. Projects in these areas involve experiments that span molecular biology, cell biology, virology, and animal models.

Selected Publications:

  1. Krebs, F. C., S. R. Miller, B. J. Catalone, P. A. Welsh, D. Malamud, M. K. Howett, and B. Wigdahl. Sodium dodecyl sulfate and C31G as microbicidal alternatives to nonoxynol 9: comparative sensitivity of primary human vaginal keratinocytes. Antimicrob Agents Chemother, 44: 1954-1960, 2000.
  2. Krebs, F. C., S. R. Miller, B. J. Catalone, R. Fichorova, D. Anderson, D. Malamud, M. K. Howett, and B. Wigdahl. Comparative in vitro sensitivities of human immune cell lines, vaginal and cervical epithelial cell lines, and primary cells to candidate microbicides nonoxynol 9, C31G, and sodium dodecyl sulfate. Antimicrob Agents Chemother, 46: 2292-2298, 2002.
  3. Catalone, B. J., T. M. Kish-Catalone, L. R. Budgeon, E. B. Neely, M. Ferguson, F. C. Krebs, M. K. Howett, M. Labib, R. Rando, and B. Wigdahl. Mouse model of cervicovaginal toxicity and inflammation for preclinical evaluation of topical vaginal microbicides. Antimicrob Agents Chemother, 48: 1837-1847, 2004.
  4. Catalone, B. J., M. L. Ferguson, S. R. Miller, D. Malamud, T. Kish-Catalone, N. J. Thakkar, F. C. Krebs, M. K. Howett, and B. Wigdahl. Prolonged exposure to the candidate microbicide C31G differentially reduces cellular sensitivity to agent re-exposure. Biomed Pharmacother, 59: 460-468, 2005.
  5. Catalone, B. J., T. M. Kish-Catalone, E. B. Neely, L. R. Budgeon, M. L. Ferguson, C. Stiller, S. R. Miller, D. Malamud, F. C. Krebs, M. K. Howett, and B. Wigdahl. Comparative safety evaluation of the candidate vaginal microbicide C31G. Antimicrob Agents Chemother, 49: 1509-1520, 2005.
  6. Catalone, B. J., S. R. Miller, M. L. Ferguson, D. Malamud, T. Kish-Catalone, N. J. Thakkar, F. C. Krebs, M. K. Howett, and B. Wigdahl. Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G. Biomed Pharmacother, 59: 430-437, 2005.
  7. Krebs, F. C., S. R. Miller, M. L. Ferguson, M. Labib, R. F. Rando, and B. Wigdahl. Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1. Biomed Pharmacother, 59: 438-445, 2005.
  8. Beer, B. E., G. F. Doncel, F. C. Krebs, R. J. Shattock, P. S. Fletcher, R. W. Buckheit, Jr., K. Watson, C. S. Dezzutti, J. E. Cummins, E. Bromley, N. Richardson-Harman, L. A. Pallansch, C. Lackman-Smith, C. Osterling, M. Mankowski, S. R. Miller, B. J. Catalone, P. A. Welsh, M. K. Howett, B. Wigdahl, J. A. Turpin, and P. Reichelderfer. In vitro preclinical testing of nonoxynol-9 as potential anti-human immunodeficiency virus microbicide: a retrospective analysis of results from five laboratories. Antimicrob Agents Chemother, 50: 713-723, 2006.
  9. Rando, R. F., S. Obara, M. C. Osterling, M. Mankowski, S. R. Miller, M. L. Ferguson, F. C. Krebs, B. Wigdahl, M. Labib, and H. Kokubo. Critical design features of phenyl carboxylate-containing polymer microbicides. Antimicrob Agents Chemother, 50: 3081-3089, 2006.
  10. Gopi, H., M. Umashankara, V. Pirrone, J. LaLonde, N. Madani, F. Tuzer, S. Baxter, I. Zentner, S. Cocklin, N. Jawanda, S. R. Miller, A. Schon, J. C. Klein, E. Freire, F. C. Krebs, A. B. Smith, J. Sodroski, and I. Chaiken. Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1. J Med Chem, 51: 2638-2647, 2008.
  11. Gopi, H., S. Cocklin, V. Pirrone, K. McFadden, F. Tuzer, I. Zentner, S. Ajith, S. Baxter, N. Jawanda, F. C. Krebs, and I. M. Chaiken. Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120. J Mol Recognit, 22: 169-174, 2009.
  12. Thakkar, N., V. Pirrone, S. Passic, W. Zhu, V. Kholodovych, W. Welsh, R. F. Rando, M. E. Labib, B. Wigdahl, and F. C. Krebs. Specific interactions between the viral coreceptor CXCR4 and the biguanide-based compound NB325 mediate inhibition of human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother, 53: 631-638, 2009.
  13. Thakkar, N., V. Pirrone, S. Passic, S. Keogan, W. Zhu, V. Kholodovych, W. Welsh, R. Rando, M. Labib, B. Wigdahl, and F. C. Krebs. Persistent interactions between biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother, 54: 1965-1972, 2010.
  14. Passic, S., M. L. Ferguson, B. J. Catalone, T. Kish-Catalone, V. Kholodovych, W. Zhu, W. Welsh, R. Rando, M. K. Howett, B. Wigdahl, M. Labib, and F. C. Krebs. Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1. Biomed Pharmacother, In press, 2010.
  15. Pirrone, V., S. Passic, B. Wigdahl, R. F. Rando, M. Labib, and F. C. Krebs. A styrene-alt-maleic acid polymer is an effective inhibitor of R5 and X4 human immunodeficiency virus type 1 infection. J Biomed Biotechnol, In press, 2010.

Contact

  • Microbiology and Immunology
  • 245 N. 15th Street
    Philadelphia, PA 19102
  • Phone: 215-762-7398
  • Fax: 215-762-7784
  • Email: Fred.Krebs@
    DrexelMed.edu