Fred Krebs

Fred Krebs

Associate Professor, Microbiology and Immunology

Ph.D., 1996, Penn State College of Medicine, Hershey, PA

245 N. 15th Street
Philadelphia, PA 19102
Tel: 215-762-7398
Fax: 215-762-7784
Email: fred.krebs@drexelmed.edu

Research Staff: Shendra Miller Passic, M. S.
Graduate Students: Vanessa Pirrone, Karissa Lozenski

Keywords:

Human immunodeficiency virus (HIV-1), Microbicide, Sexually transmitted disease (STD), Polybiguanide

Research Interests:

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 deter the consistent use of condoms and limit their effectiveness. As a consequence, increasing efforts have been directed toward the development of topical agents, collectively termed microbicides, that could be used within the female reproductive tract to prevent HIV-1 transmission. Ideally, microbicides would be (i) effective against HIV-1, as well as other sexually transmitted disease (STD) pathogens (including HSV-2 and HPV), (ii) nontoxic, (iii) inexpensive, and (iv) easy to use by the female partner.

Our identification of potential microbicidal compounds follows an integrated and multi-faceted program of investigation conducted in collaboration with investigators at Novaflux Biosciences, Inc. (Princeton, NJ, USA). Some of our efforts in the area of microbicide development are focused on a family of compounds called polybiguanides (PBGs), which are polymeric, polycationic molecules distinguished by biguanide repeat units separated by hydrocarbon chain linkers. Relationships between PBG structure and compound efficacy are being pursued using PBG-based compounds designed and synthesized in a logical and hypothesis-driven manner. Our lead compound in these studies is polyethylene hexamethylene biguanide (PEHMB), which combines considerable activity against HIV-1 with low in vitro and in vivo toxicity.

PBGs and other agents under consideration as microbicidal agents are evaluated using a wide range of experimental approaches. Candidate microbicidal compounds are first tested in an array of in vitro assays to document cytotoxicity and activity against both cell-free and cell-associated HIV-1. Subsequent experiments using a mouse model of toxicity examine the impact of candidate microbicidal compounds and formulations on cervicovaginal epithelial tissue integrity and inflammation. Molecular and cell biology-based approaches, including microarray analyses and laser capture microdissection (LCM), are also used to examine immune- and stress-related changes in gene expression associated with compound application. Additional studies define the mechanisms through which PBGs and other compounds are able to interfere with HIV-1 infection. All of these investigations are designed to significantly advance the pre-clinical development of microbicidal compounds under investigation 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.

Selected Publications:

Howett, M.K., E.B. Neely, N.D. Christensen, B. Wigdahl, F.C. Krebs, D. Malamud, S.D. Patrick, M.D. Pickel, P.A. Welsh, C.A. Reed, M.G. Ward, L.R. Budgeon, and J. W. Kreider. A broad-spectrum microbicide with virucidal activity against sexually transmitted viruses. Antimicrob Agents Chemother, 43:314-321, 1999.
Krebs, F.C., S.R. Miller, D. Malamud, M.K. Howett, and B. Wigdahl. Inactivation of human immunodeficiency virus type 1 by nonoxynol-9, C31G, or an alkyl sulfate, sodium dodecyl sulfate. Antiviral Res, 43:157-173, 1999.
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.
Catalone, B.J., Krebs, F. C., Labib, M., and B. Wigdahl. Broad-spectrum microbicides as a strategy for reducing sexually transmitted disease prevalence and HIV-1 transmission. Res. Adv. in Antimicrob. Agents Chemother., 2: 55-80, 2001.
Krebs, F.C., Miller, S. R., Catalone, B. J., Fichorova, R., Anderson, D., Malamud, D., Howett, M. K., 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.
Nonnemacher, M.R., Hogan, T. H., Quiterio, S. J., Wigdahl, B., Henderson, A., and F. C. Krebs. Identification of binding sites for members of the CCAAT/enhancer binding protein transcription factor family in the simian immunodeficiency virus long terminal repeat. Biomed. Pharmacother., 57: 34-40, 2003.
Kensinger, R. D., Catalone, B. J., Krebs, F. C., Wigdahl, B., and C. -L. Schengrund. Novel polysulfated galactose-derivatized dendrimers as binding antagonists of human immunodeficiency virus type 1 infection. Antimicrob. Agents Chemother., 48: 1614-1623, 2004.
Burdo, T. H., Nonnemacher, M. R., Irish, B. P., Choi, C. H., Krebs, F. C., Gartner, S., and B. Wigdahl. High-affinity interaction between HIV-1 Vpr and specific sequences that span the C/EBP and adjacent NF-κB sites within the HIV-1 LTR correlate with HIV-1-associated dementia. DNA and Cell Biology, 23: 261-269, 2004.
Catalone, B. J., Kish-Catalone, T. M., Budgeon, L. R., Neely, E. B., Ferguson, M., Krebs, F. C., Howett, M. K., Labib, M., Rando, R., and B. Wigdahl. Mouse model of cervicovaginal toxicity and inflammation for preclinical evaluation of topical vaginal microbicides. Antimicrob. Agents Chemother., 48: 1837-1847, 2004.
Catalone, B. J., Ferguson, M. L., Miller, S. R., Malamud, D., Kish-Catalone, T., Thakkar, N. J., Krebs, F. C., Howett, M. K., and B. Wigdahl. Prolonged exposure to the candidate microbicide C31G differentially reduces cellular sensitivity to agent re-exposure. Biomed. Pharmacother., 59: 460-468, 2005.
Catalone, B. J., Kish-Catalone, T. M., Neely, E. B., Budgeon, L. R., Ferguson, M. L., Stiller, C., Miller, S. R., Malamud, D., Krebs, F. C., Howett, M. K., and B. Wigdahl. Comparative safety evaluation of the candidate vaginal microbicide C31G. Antimicrob. Agents Chemother., 49: 1509-1520, 2005.

Catalone, B. J., Miller, S. R., Ferguson, M. L., Malamud, D., Kish-Catalone, T., Thakkar, N. J., Krebs, F. C., Howett, M. K., 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.

Krebs, F. C., Miller, S. R., Ferguson, M. L., Labib, M., Rando, R. F., and B. Wigdahl. Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1. Biomed. Pharmacother., 59: 438-445, 2005.

Beer, B. E., Doncel, G. F., Krebs, F. C., Shattock, R. J., Fletcher, P. S., Buckheit, Jr., R. W., Watson, K., Dezzutti, C. S., Cummins, J. E., Bromley, E., Richardson-Harman, N., Pallansch, L. A., Lackman-Smith, C., Osterling, C., Mankowski, M., Miller, S. R., Catalone, B. J., Welsh, P. A., Howett, M. K., Wigdahl, B., Turpin, J. A., 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.

Rando, R. F., Obara, S., Osterling, M. C., Mankowski, M., Miller, S. R., Ferguson, M. L., Krebs, F. C., Wigdahl, B., Labib, M., and H. Kokubo. Critical design features of phenyl carboxylate-containing polymer microbicides. Antimicrob. Agents Chemother., 50: 3081-3089, 2006.