Research Summary

The Perlin lab is interested in mechanisms of antifungal drug resistance, rapid detection of bloodstream pathogens in high-risk patients, discovery of novel molecules to combat tuberculosis, and the development of small animal models for respiratory pathogens.

Mechanisms of antifungal drug resistance. Fungal infections are a significant cause of morbidity and mortality in severely ill patients, and their impact is exacerbated by a failure to rapidly diagnose and effectively treat these infections. The widespread use of antifungal agents has resulted in selection of naturally resistant fungal species, as well as the emergence of resistance in susceptible species. Treatment of fungal disease is hampered by the availability of few classes of antifungal drugs. Recently, a new class of echinocandin drugs was introduced clinically that target the fungal cell wall by blocking B-(1,3)-D-glucan synthase. As patient exposure to echinocandin class drugs expands, it is anticipated that the number of clinical isolates with drug resistance will rise. The echinocandins are the first new major antifungal drug class to enter the market in decades, and it is vital to understand the nature of resistance mechanisms. Recently, we reported that amino acid substitutions in two regions of Fks1p, a primary component of the glucan synthase complex, could account for resistance in laboratory and clinical isolates of Candida albicans and Aspergillus fumigatus. The objective of this program is to explore in detail by genetic and biochemical means the role of Fks1p as an important new mechanism for clinical resistance to echinocandin drugs. This work is funded by funds from the NIH and Pharma.

Rapid detection of bloodstream infections. Blood stream infections (BSIs) are a significant cause of morbidity and mortality in the USA with an estimated 250,000 cases annually. Early antimicrobial therapy is critical to a favorable outcome for patients with BSIs. Current diagnostic methods can take from 24 hours up to a week for positive pathogen identification and even longer for drug susceptibility. Reducing the time period from specimen collection to species identification and antimicrobial susceptibility is essential for improving outcome for patients. No registered molecular diagnostic tool is currently available to clinical microbiology laboratories. In partnership with bioMerieux, a global leader in clinical diagnostics, we are developing a next-generation nucleic acid based NASBA-Molecular Beacons platform for rapid identification of bacterial and fungal pathogens, and associated drug resistance in selected organisms. Clinical sites in the USA and Europe have been selected to evaluate the new platform. This program, joining PHRI's technical expertise in molecular beacon probe development with bioMerieux NASBA technology and clinical diagnostic product development, along with outstanding clinical partners, is intended to improve the outcome for sepsis patients worldwide. This work is supported by funds from the NIH.

Drug discovery: Novel molecules to combat tuberculosis. Drug-resistance often limits treatment of infectious diseases such as tuberculosis. Biologically, a large number of amino acids on key target enzymes can mutate to confer drug-resistant phenotypes under the selective pressure of chemotherapy. Infectious agents like tuberculosis represent a serious challenge to the current strategy of drug discovery. The goal of this work is to discover drug candidates that block replication and/or survival of tubercle bacilli by interfering with non-essential host machinery that is required by the microorganism. In this way, the microorganism is controlled, but it never develops primary resistance to the drug. This concept is derived from a therapeutic strategy in Chinese medicine called Wei-Qi (protection from inside). Our collaborator Dr. Jian-Dong Jiang (Chinese Academy of Medical Sciences, Beijing) has identified chemical entities (from natural products) that inhibit microbial replication through modification of cellular processes. Potential targets for drug therapy were identified by evaluating cellular proteins that are not crucial for the cell survival, but are essential for the replication and/or survival of M. tuberculosis. This work is supported by a grant from the Gates Foundation.

Animal models for respiratory pathogens. We are actively engaged in developing and running small animal infection models for a wide range of investigators from 26 member institutions, as part of our role as a Small Animal Core for the NIH, Region II, Regional, Center of Excellence in Biodefense and Emerging Infectious Diseases. This work is performed on both a collaborative and service basis. It is supported by NIH funds and user fees.




Recent Publications

Garcia-Effron, G., Park, S. and Perlin, D.S. 2008.
Evaluating breakpoints for echinocandin drugs through a kinetic analysis of inhibition of fks1 mutant glucan synthases from Candida albicans.
In press.

Kamboj, M., Gerbin, M., Huang, D., Brennan, C., Stiles, J., Park, S., Kiehn, T., Perlin, D., Pamer, E.J., and Sepkowitz, K.A. 2008.
Clinical Characterization of human metapneumovirus infection among patients with cancer.
J. Infect. In Press.

Chattopadhyay, A., Park, S., Delmas, G., Suresh, R., Senina, S., Perlin, D.S. and Rose, J.K. 2008.
Single-dose, virus-vectored vaccine protection against Yersinia pestis challenge: CD4+ cells are required at the time of challenge for optimal protection.
Vaccine 26(50):6329-37.

Garcia-Effron, G., Kontoyiannis, D.P., Lewis, R.E. and Perlin, D.S. 2008.
Echinocandin-resistant C. tropicalis breakthrough fungemia in high risk hematology patients.
Accepted.

Wiederhold,N.P., Grabinski, J.L. Garcia-Effron, G., Perlin, D.S. and Lee, S.A. 2008.
Pyrosequencing to Detect Mutations in FKS1 that Confer Reduced Echinocandin Susceptibility in Candida albicans.
Antimicrob Agents Chemother 52(11):4145.

Arendrup, MC, Perkhofer, S, Howard, S.J., Garcia-Effron, G., Vishukumar, A., Perlin D., and Lass-Flörl, C. 2008.
Establishing in vitro-in vivo correlations for Aspergillus fumigatus: the challenge of azoles versus echinocandins.
Antimicrob Agents Chemother. 52(10):3504-11.

Cramer, R.A., Perfect, B.Z., Pinchai, N., Park, S., Perlin, D.S., Heitman, J., Perfect, J.R. and Steinbach, W.J. 2008.
The Aspergillus fumigatus crzA gene is involved in conidia germination, hyphal growth, and required for fungal pathogenesis in an experimental murine model of invasive pulmonary aspergillosis.
Eukaryot Cell. 7:1085-97.

Perlin, D.S. 2008.
Emerging antifungal resistance.
J. Infect. Dis. Accepted

Cleary, J.D.,Garcia-Effron, G., Chapman, S.W. and Perlin, D.S. 2008.
Reduced Candida glabrata Susceptibility Secondary to a FKS2 Mutation Developed During Candidemia Treatment.
Antimicrobiol. Agents and Chemother. Antimicrob Agents Chemother. 52(6):2263-5.

Garcia-Effron, G., Katiyar, S.K., Edlind, T.D., Park, S. and Perlin, D.S. 2008.
A naturally-occurring proline to alanine polymorphism in Candida parapsilosis and sibling species accounts for echinocandin reduced susceptibility.
Antimicrob Agents Chemother. 52(7):2305-12.

Perlin D.S. and Zhao, Y. 2008.
Molecular Diagnostic Platforms for Detecting Aspergillus.
Med Mycol. 2008 Jun 12:1-10.

Garcia-Effron, G., Dilger, A., Alcazar-Fuoli, L., Park, S., Mellado, E. and Perlin, D.S. 2008.
Rapid detection of triazole resistance in Aspergillus fumigatus.
J Clin Microbiol. 46(4):1200-6.

Hohl, T.M. Feldmesser, M., Perlin, D.S. and Pamer, E.G. 2008.
Caspofungin modulates inflammatory responses to Aspergillus fumigatus through stage-specific effects on fungal ?-glucan exposure.
J Infect Dis. 198(2):176-85.

Rocha, E.M.F., Garcia-Effron, G.M., Park, S. and Perlin, D.S. 2007.
A Ser678Pro Substitution in Fks1p Confers Resistance to Echinocandin Drugs in Aspergillus fumigatus.
Antimicrob Agents Chemother. 51(11):4174-6.

Perlin, D.S. 2007.
Resistance to echinocandin-class antifungal drugs.
Drug Resis.Updates. 10, 121-130.

Nielsen-Kahn, J., Garcia-Effron,G., Park,S., Marr, K.A. and Perlin, D.S. 2007.
Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase.
Antimicrob Agents Chemother. 51(5):1876-8.

Paderu, P., Garcia-Effron, G., Balashov, S., Delmas, G., Park, S. and Perlin, D.S. 2007.
Serum differentially alters the antifungal properties echinocandin drugs.
Antimicrob Agents Chemother. 51(6):2253-6.

Beckloff N, Laube D, Castro T, Furgang D, Park S, Perlin D, Clements D, Tang H, Scott RW, Tew GN, Diamond G. 2007.
Activity of an antimicrobial peptide mimetic against planktonic and biofilm cultures of oral pathogens.
Antimicrob Agents Chemother. 51(11):4125-32.

Miller CD, Lomaestro BW, Park S, Perlin DS 2006.
Progressive Esophagitis Caused by Candida albicans with Reduced Susceptibility to Caspofungin.
Pharmacotherapy. 26(6):877-80.

Palin, A., Chattopadhyay, A., Park, S., Delmas, G., Suresh, R., Senina, S., Perlin, D.S., and Rose, J.K. 2007.
An optimized vaccine vector based recombinant vesicular stomatitis virus gives high-level, long term protection against Yersinia pestis challenge.
Vaccine. 25(4):741-50.

BOOKS and CHAPTERS

Drlica, K., J.-Y. Wang, M. Malik, T. Lu, C. Logan, S. Park, X. Li, D.S. Perlin, and X. Zhao. 2007.
Antimicrobial Resistance and Implications for the 21st Century, Series: Emerging Infectious Diseases of the 21st Century
Fong, I.W.; Drlica, Karl (Eds.) Springer, NY.

Beauvais, A., Perlin, D.S., and Latgé, J.P. 2007.
Role of (1-3) glucan in Aspergillus fumigatus and other human fungal pathogens. Fungi in the Environment Series: British Mycological Society Symposia (No. 25)
Edited by Geoff Gadd, Sarah C. Watkinson and Paul Dyer, University of Oxford pp. 269-288.

Perlin D.S. 2008.
Rapid Detection of Pathogens Bioterror: The Weaponization of Infectious Diseases.
Larry I. Lutwick MD Suzanne M. Lutwick RN, BS, MPH Humana Press.

Perlin, D.S. 2007.
Emerging Fungal Diseases. Emerging Infectious Diseases: Trends and Issues, 2nd ed.
Editors: F. Lashley and J.D. Durham, Springer, NY.

Perlin, D.S. 2007.
Multiplex detection of mutations. Methods in Molecular Biology.
Editors: A. Marx and O. Seitz. The Humana Press Inc. NJ.

Perlin, D.S. 2007.
Application of real-time PCR to the diagnosis of invasive fungal infections. Real-time PCR.
Editors: K. Edwards, J. Logan and N. Saunders. Horizon Scientific Press. Norwich, UK.

Perlin, D.S. 2008.
Antifungal Drug Resistance in Developing Countries. Antimicrobial Resistance in Developing Countries.
Editors: D.K. Byarugaba and A. Sosa. Springer, USA.

Perlin, D.S. and Mellado, E. 2008.
Antifungal mechanisms of action and resistance. Aspergillus and Aspergillosis.
Editors: W.J. Steinbach and J-P Latge, ASM Press.

Perlin, D.S. and W. Hope. 2009.
Echinocandins. Aspergillosis: From diagnosis to prevention.
Springer. The Netherlands.

PubMed Lisitings>




C.V.

Education
Brandeis University, Waltham, MA, B.A., 1976 (Biology); Cornell University, Ithaca, NY, Ph.D., 1980 (Plant Physiology); Yale University School of Medicine, New Haven, CT, Post-doc., 1980-82 (Biochemistry, Genetics); Univ. of Rochester Sch. Med. & Dent., Rochester, NY, Post-doc., 1983-85 (Biochemistry).Associate Member, PHRI, 1990; Assistant member, PHRI, 1985.

Recent Honors
Fellow, New York Academy of Sciences, 2005.

Positions
Director, PHRI Center, New Jersey Medical School, 2006; President, PHRI, April 2005; Scientific Director, PHRI, 1992; Professor, Microbiology and Molecular Genetics- UMDNJ-New Jersey Medical School; New York University Medical School, 2003, Adjunct Assistant Member, 1986.

Professional Activities
Editorial Board, Journal Bioenergetics and Biomembranes; Microb. Drug Resistance; Editorial Board, Elec. J. Biotechnology; Board Member, Aaron Diamond AIDS Research Center, May 2005; SAB member, Elusys Pharma; Myconsotica, Ltd. and BioDelivery Sciences; Scientific Advisor, US Senate Finance Committee- Investigation of Anthrax Outbreak, Dec. 2001-March 2002; Sen. Jon S. Corzine Healthcare Issues Task Force, Aug. 2002-; NJ-ECC, consulting microbiologist, anthrax decontamination Hamilton Post Office; Adv. Comm. 1993; New York Academy of Sciences (NYAS), Frontiers in Science-Infectious Diseases, July 2003; New York City Bioterrorism and Emerging Pathogens Advisory Committee; Trans-RCE Non-Human Primate Aerobiology Steering Committee; Organizer, Combating Plague, NYAS, Oct. 2005; Drug resistance in Infectious Diseases, NYAS, April 2005; Invasive Aspergillosis Symposium, NYAS, Dec. 2006; Scientific Steering Committee, 3rd Advances Against Aspergillosis, Jan. 08.