The Perlin lab is interested in mechanisms of antifungal drug resistance, rapid detection of bloodstream and respiratory pathogens in high-risk patients, and the application 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. The newest class is the echinocandin drugs, which target the fungal cell wall by blocking B-(1,3)-D-glucan synthase. As patient exposure to echinocandin class drugs has expanded, the number of clinical failures being reported has risen. Thus, it is vital to understand the nature of resistance mechanisms. We have demonstrated that amino acid substitutions in two regions of Fks1p, a primary component of the glucan synthase complex, account for resistance in 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 Fks as an important new mechanism for clinical resistance to echinocandin drugs. These studies have been important to understand the nature of echinocandin drug resistance and to help the CLSI establish new clinical breakpoints for susceptibility and resistance. The Perlin Lab serves as a Pfizer supported Global Reference Center for echinocandin resistance.
We are also studying the mechanism of triazole resistance in Aspergillus fumigatus in collaboration with Dr. David Denning, Director of the National Aspergillosis Center, Manchester, UK. We have characterized a wide array of mutations in the Cyp51A gene, which confers differential resistance to itraconazole, voriconazole and posaconazole. The objective of this work is to evaluate trends in resistance and develop approaches for rapid diagnosis of drug resistant infections and explore drug/dosing regimens that overcome resistance. This work is funded by the NIH and Pharma.
Rapid detection of respiratory and bloodstream infections. Blood stream infections (BSIs) are a significant cause of morbidity and mortality in the USA. 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. We are developing next-generation nucleic acid PCR- and NASBA-based molecular beacon platforms for rapid identification of bacterial and fungal pathogens, and associated drug resistance in selected organisms including KPC, MRSA, VRE, C. difficile, Candida spp. and Aspergillus spp. We are also developing panels for rapid diagnosis of a variety of common respiratory viruses including IFA, IFB, RSV, AdV and PIV. The new diagnostic tools are being validated in prospective clinical validation studies with clinical partners. This work is funded by funds from the NIH and Pharma.
Animal models for respiratory pathogens. We are actively engaged in developing and running BSL2 and BSL3 small animal infection models for a wide range of investigators from the Northeast Biodefense Consortium, 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, and it is supported by NIH funds and user fees.
Zhao Y, Stensvold CR, Perlin DS, Arendrup MC (2013) Azole resistance in Aspergillus fumigatus from bronchoalveolar lavage fluid samples of patients with chronic diseases. J Antimicrob Chemother 68: 1497-1504. PMI: 23463213
Zhao Y, Petraitiene R, Walsh TJ, Perlin DS (2013) A real-time PCR assay for rapid detection and quantification of Exserohilum rostratum, a causative pathogen of fungal meningitis associated with injection of contaminated methylprednisolone. J Clin Microbiol 51: 1034-1036. PMI: 23303500
Zhao Y, Perlin DS (2013) Quantitative detection of Aspergillus spp. by real-time nucleic acid sequence-based amplification. Methods Mol Biol 968: 83-92. PMI: 23296887
Kontoyiannis DP, Perlin DS, Roilides E, Walsh TJ (2013) What can we learn and what do we need to know amidst the iatrogenic outbreak of Exserohilum rostratum meningitis? Clin Infect Dis 57: 853-859. PMI: 23650291
Jimenez-Ortigosa C, Paderu P, Motyl MR, Perlin DS (2013) Enfumafungin derivative MK-3118 shows increased in vitro potency against clinical echinocandin resistant Candida spp. and Aspergillus spp. isolates. Antimicrob Agents Chemother. PMI: 24323472
Clancy CJ, Chen L, Hong JH, Cheng S, Hao B, Shields RK, Farrell AN, Doi Y, Zhao Y, Perlin DS, Kreiswirth BN, Nguyen MH (2013) Mutations of the ompK36 porin gene and promoter impact responses of sequence type 258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem-colistin. Antimicrob Agents Chemother 57: 5258-5265. PMI: 23939888
Alexander BD, Johnson MD, Pfeiffer CD, Jimenez-Ortigosa C, Catania J, Booker R, Castanheira M, Messer SA, Perlin DS, Pfaller MA (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56: 1724-1732. PMI: 23487382
Zhao Y, Paderu P, Park S, Dukhan A, Senter M, Perlin DS (2012) Expression turnover profiling to monitor the antifungal activities of amphotericin B, voriconazole and micafungin against Aspergillus fumigatus. Antimicrob Agents Chemother. PMI: 22314535
Garcia-Effron G, Canton E, Peman J, Dilger A, Roma E, Perlin DS (2012) Epidemiology and echinocandin susceptibility of Candida parapsilosis sensu lato species isolated from bloodstream infections at a Spanish university hospital. J Antimicrob Chemother 67: 2739-2748. PMI: 22868644
Wang Y, Liu TB, Delmas G, Park S, Perlin D, Xue C (2011) Two major inositol transporters and their role in cryptococcal virulence. Eukaryot Cell 10: 618-628. PMI: 21398509
Slater JL, Howard SJ, Sharp A, Goodwin J, Gregson LM, Alastruey-Izquierdo A, Arendrup MC, Warn PA, Perlin DS, Hope WW (2011) Disseminated Candidiasis caused by Candida albicans with amino acid substitutions in Fks1 at position Ser645 cannot be successfully treated with micafungin. Antimicrob Agents Chemother 55: 3075-3083. PMI: 21502627
Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS (2011) Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14: 164-176. PMI: 21353623
Perlin DS (2011) Echinocandin-Resistant Candida: Molecular Methods and Phenotypes. Curr Fungal Infect Rep 5: 113-119. PMI: 0
Perlin DS (2011) Current perspectives on echinocandin class drugs. Future Microbiol 6: 441-457. PMI: 21526945
Hauser PM, Bille J, Lass-Florl C, Geltner C, Feldmesser M, Levi M, Patel H, Muggia V, Alexander B, Hughes M, Follett SA, Cui X, Leung F, Morgan G, Moody A, Perlin DS, Denning DW (2011) Multicenter, prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay. J Clin Microbiol 49: 1872-1878. PMI: 21367988
Garcia-Effron G, Park S, Perlin DS (2011) Improved detection of Candida sp. fks hot spot mutants by using the method of the CLSI M27-A3 document with the addition of bovine serum albumin. Antimicrob Agents Chemother 55: 2245-2255. PMI: 21383097
Garcia-Effron G, Canton E, Peman J, Dilger A, Roma E, Perlin DS (2011) Assessment of two new molecular methods for identification of Candida parapsilosis sensu lato species. J Clin Microbiol 49: 3257-3261. PMI: 21795509
Endimiani A, Hujer KM, Hujer AM, Kurz S, Jacobs MR, Perlin DS, Bonomo RA (2011) Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia? Clin Infect Dis 52 Suppl 4: S373-383. PMI: 21460299
Denning DW, Perlin DS (2011) Azole resistance in Aspergillus: a growing public health menace. Future Microbiol 6: 1229-1232. PMI: 22082283
Denning DW, Park S, Lass-Florl C, Fraczek MG, Kirwan M, Gore R, Smith J, Bueid A, Moore CB, Bowyer P, Perlin DS (2011) High-frequency triazole resistance found In nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis 52: 1123-1129. PMI: 21467016
Cagas SE, Jain MR, Li H, Perlin DS (2011) The proteomic signature of Aspergillus fumigatus during early development. Mol Cell Proteomics 10: M111 010108. PMI: 21825280
Cagas SE, Jain MR, Li H, Perlin DS (2011) Profiling the Aspergillus fumigatus proteome in response to caspofungin. Antimicrob Agents Chemother 55: 146-154. PMI: 20974863
Ben-Ami R, Garcia-Effron G, Lewis RE, Gamarra S, Leventakos K, Perlin DS, Kontoyiannis DP (2011) Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance. J Infect Dis 204: 626-635. PMI: 21791665
Arendrup MC, Rodriguez-Tudela JL, Park S, Garcia-Effron G, Delmas G, Cuenca-Estrella M, Gomez-Lopez A, Perlin DS (2011) Echinocandin susceptibility testing of Candida spp. Using EUCAST EDef 7.1 and CLSI M27-A3 standard procedures: analysis of the influence of bovine serum albumin supplementation, storage time, and drug lots. Antimicrob Agents Chemother 55: 1580-1587. PMI: 21245440
Arendrup MC, Park S, Brown S, Pfaller M, Perlin DS (2011) Evaluation of CLSI M44-A2 disk diffusion and associated breakpoint testing of caspofungin and micafungin using a well-characterized panel of wild-type and fks hot spot mutant Candida isolates. Antimicrob Agents Chemother 55: 1891-1895. PMI: 21357293
Zhao Y, Park S, Warn P, Shrief R, Harrison E, Perlin DS (2010) Detection of Aspergillus fumigatus in a rat model of invasive pulmonary aspergillosis by real-time nucleic acid sequence-based amplification. J Clin Microbiol 48: 1378-1383. PMI: 20129972
Zhang YQ, Gamarra S, Garcia-Effron G, Park S, Perlin DS, Rao R (2010) Requirement for ergosterol in V-ATPase function underlies antifungal activity of azole drugs. PLoS Pathog 6: e1000939. PMI: 20532216
Wang YP, Liu F, He HW, Han YX, Peng ZG, Li BW, You XF, Song DQ, Li ZR, Yu LY, Cen S, Hong B, Sun CH, Zhao LX, Kreiswirth B, Perlin D, Shao RG, Jiang JD (2010) Heat stress cognate 70 host protein as a potential drug target against drug resistance in hepatitis B virus. Antimicrob Agents Chemother 54: 2070-2077. PMI: 20176893
Tuohy MJ, Reja V, Park S, Perlin DS, Wnek M, Procop GW, Yen-Lieberman B (2010) Use of a high-resolution melt assay to characterize codon 54 of the cyp51A gene of Aspergillus fumigatus on a Rotor-Gene 6000 instrument. Antimicrob Agents Chemother 54: 2248-2251. PMI: 20194699
Rodriguez-Tudela JL, Gomez-Lopez A, Arendrup MC, Garcia-Effron G, Perlin DS, Lass-Florl C, Cuenca-Estrella M (2010) Comparison of caspofungin MICs by means of EUCAST method EDef 7.1 using two different concentrations of glucose. Antimicrob Agents Chemother 54: 3056-3057. PMI: 20479199
Redelman-Sidi G, Sepkowitz KA, Huang CK, Park S, Stiles J, Eagan J, Perlin DS, Pamer EG, Kamboj M (2010) 2009 H1N1 influenza infection in cancer patients and hematopoietic stem cell transplant recipients. J Infect 60: 257-263. PMI: 20138188
Puttikamonkul S, Willger SD, Grahl N, Perfect JR, Movahed N, Bothner B, Park S, Paderu P, Perlin DS, Cramer RA, Jr. (2010) Trehalose 6-phosphate phosphatase is required for cell wall integrity and fungal virulence but not trehalose biosynthesis in the human fungal pathogen Aspergillus fumigatus. Mol Microbiol. PMI: 20545865
Pfeiffer CD, Garcia-Effron G, Zaas AK, Perfect JR, Perlin DS, Alexander BD (2010) Breakthrough invasive candidiasis in patients on micafungin. J Clin Microbiol 48: 2373-2380. PMI: 20421445
Lin JS, Park S, Adamovicz JJ, Hill J, Bliska JB, Cote CK, Perlin DS, Amemiya K, Smiley ST (2010) TNFalpha and IFNgamma contribute to F1/LcrV-targeted immune defense in mouse models of fully virulent pneumonic plague. Vaccine 29: 357-362. PMI: 20840834
Koster F, Perlin DS, Park S, Brasel T, Gigliotti A, Barr E, Myers L, Layton RC, Sherwood R, Lyons CR (2010) Milestones in progression of primary pneumonic plague in cynomolgus macaques. Infect Immun 78: 2946-2955. PMI: 20385751
Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H (2010) Novel FKS mutations associated with echinocandin resistance in Candida species. Antimicrob Agents Chemother 54: 2225-2227. PMI: 20145084
Gamarra S, Rocha EM, Zhang YQ, Park S, Rao R, Perlin DS (2010) Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans. Antimicrob Agents Chemother 54: 1753-1761. PMI: 20194694
Do Y, Koh H, Park CG, Dudziak D, Seo P, Mehandru S, Choi JH, Cheong C, Park S, Perlin DS, Powell BS, Steinman RM (2010) Targeting of LcrV virulence protein from Yersinia pestis to dendritic cells protects mice against pneumonic plague. Eur J Immunol 40: 2791-2796. PMI: 20812236
Boyer JL, Sofer-Podesta C, Ang J, Hackett NR, Chiuchiolo MJ, Senina S, Perlin D, Crystal RG (2010) Protective immunity against a lethal respiratory Yersinia pestis challenge induced by V antigen or the F1 capsular antigen incorporated into adenovirus capsid. Hum Gene Ther 21: 891-901. PMI: 20180652
Arendrup MC, Garcia-Effron G, Lass-Florl C, Lopez AG, Rodriguez-Tudela JL, Cuenca-Estrella M, Perlin DS (2010) Echinocandin susceptibility testing of Candida species: comparison of EUCAST EDef 7.1, CLSI M27-A3, Etest, disk diffusion, and agar dilution methods with RPMI and isosensitest media. Antimicrob Agents Chemother 54: 426-439. PMI: 19884370
Zhao Y, Park S, Kreiswirth BN, Ginocchio CC, Veyret R, Laayoun A, Troesch A, Perlin DS (2009) Rapid real-time nucleic Acid sequence-based amplification-molecular beacon platform to detect fungal and bacterial bloodstream infections. J Clin Microbiol 47: 2067-2078. PMI: 19403758
Sofer-Podesta C, Ang J, Hackett NR, Senina S, Perlin DS, Crystal RG, Boyer JL (2009) Adenovirus-mediated delivery of an anti-V antigen monoclonal antibody protects mice against a lethal Yersinia pestis challenge. Infect Immun 77: 1561-1568. PMI: 19124600
Perlin DS (2009) Antifungal drug resistance: do molecular methods provide a way forward? Curr Opin Infect Dis 22: 568-573. PMI: 19741524
Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, Laverdiere M, Arendrup MC, Perlin DS, Denning DW (2009) Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis 15: 1068-1076. PMI: 19624922
Garcia-Effron G, Park S, Perlin DS (2009) Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints. Antimicrob Agents Chemother 53: 112-122. PMI: 18955538
Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS (2009) Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob Agents Chemother 53: 3690-3699. PMI: 19546367
Arendrup MC, Garcia-Effron G, Buzina W, Mortensen KL, Reiter N, Lundin C, Jensen HE, Lass-Florl C, Perlin DS, Bruun B (2009) Breakthrough Aspergillus fumigatus and Candida albicans double infection during caspofungin treatment: laboratory characteristics and implication for susceptibility testing. Antimicrob Agents Chemother 53: 1185-1193. PMI: 19104024
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. 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
Perlin, D.S. 2008. 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. and W. Hope. 2009. Echinocandins. Aspergillosis: From diagnosis to prevention. Springer. The Netherlands.
Drlica, K. and Perlin, D.S. 2010 Antibiotic Resistance: Understanding and Responding to an Emerging Crisis. Published 2010 by FT Press.
Lewis, R. and Perlin, D.S. 2011. Fungal Drug Resistance and Pharmacologic Considerations of Dosing Newer Antifungal Therapies. "Management of Infections in Cancer Patients" Current Clinical Oncology Safdar, Amar (Ed.) 1st Edition.
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.
Fellow, New York Academy of Sciences, 2005.
Director, PHRI Center, New Jersey Medical School, 2006; President, PHRI, April 2005; Scientific Director, PHRI, 1992; Professor, Microbiology and Molecular Genetics- New Jersey Medical School - Rutgers, The State University of New Jersey; New York University Medical School, 2003, Adjunct Assistant Member, 1986.
Editorial Boards: Drug Resistance Updates, 2010-; Microb. Drug Resistance; Medical Mycology (special); Journal Bioenergetics and Biomembranes, 1991-; Elec. J. Biotechnology, 1997-; SAB member: BioDelivery Sciences, Elusys Pharma, May 2005; Myconostica, Oct. 2006; Board Member, Aaron Diamond AIDS Research Center, May 2005; Merck FDA Advisory Group for Caspofungin Sept. 2002; Merck Opinion Leader, April 2001; Oct 2005; Sept. 2007; Jan. 2008; Pfizer Opinion leader, May 2007; NIH Study Sections (13 since 2002).Scientific Advisor, US Senate Finance Committee- Investigation of Anthrax Outbreak, Dec. 2001-March 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; Blavatnik Young Investigator Award Committee 2007,2008; Trans-RCE Non-Human Primate Aerobiology Steering Committee; Organizer, Combating Plague, NYAS, Oct. 2005; Organizer, Drug resistance in Infectious Diseases, NYAS, April 2005; Organizer, Invasive Aspergillosis Symposium, NYAS, Dec. 2006; Scientific Steering Committee, 3rd Advances Against Aspergillosis, Jan. 2008; Jan 2009; Jan 2012; CLSI Antifungal Group, 2010.