| Lab Members
|| Visiting Scientists
| Dr. Yanan Zhao
|| Dr. Soo-Hyun Kim
| Dr. Cristina Jiménez-Ortigosa
|| Ms. Milena Kordalewska
| Dr. Kelley Healey
| Dr. Erika Shor
| Dr. Enriko Dolgov
| Dr. Yevgeniy Senin
| Ms. Padmaja Paderu
| Mr. Guillaume Delmas
The Perlin lab is interested in mechanisms of antifungal drug resistance, rapid detection of drug resistant bloodstream and respiratory pathogens in high-risk patients, drug discovery against multidrug resistant bacterial infections, 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. The widespread use of antifungal agents has resulted in selection of less susceptible fungal species, as well as the emergence of resistance in susceptible species. Echinocandins are important antifungal agents for the treatment of patients with Candida infections. These drugs target the fungal cell wall by blocking b-1,3-D-glucan synthase, but therapeutic failures are increasingly reported, especially with C. glabrata. We have demonstrated that amino acid substitutions in the catalytic Fks subunits of glucan synthase account for resistance in clinical isolates of Candida spp. To better understand echinocandin resistance, cellular factors are being examined in in vitro and in vivo models for their role in emergence of fks-mediated echinocandin resistance. Specifically, compensatory cell wall stress responses, DNA repair, azole resistance, and novel genes/pathways are being profiled. This work exploits engineered isogenic mutant strains and genetically matched susceptible and fks-resistant clinical isolates of C. glabrata. These latter isolates will be profiled for changes in the genome and transcriptome to assess the importance of known mechanisms and elucidate new genetic mechanism underlying resistance emergence. It is anticipated that this information will provide important new insights and potential intervention strategies to overcome or prevent the emergence of echinocandin resistance. The Perlin Lab serves as an Astellas-supported Global Reference Center for echinocandin resistance
We are also studying mechanisms of triazole resistance in chronic Aspergillus fumigatus infections 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 NIH/NIAID grant 1R01AI109025 and a grant from Astellas.
Rapid detection of respiratory and bloodstream infections and associated resistance markers. 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 RNA-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. The new diagnostic tools are being validated in prospective clinical validation studies with clinical partners.
Detection of unculturable cryptic infections causing chronic diseases is a major concern for medical mycology. A. fumigatus causes a wide spectrum of diseases including allergic syndromes, chronic pulmonary aspergillosis and acute invasive aspergillosis. The rapid increase in triazole resistant Aspergillus infections is a growing public health and patient management concern. Our goal is to elucidate key microbial factors influencing resistance associated with chronic and acute Aspergillus infections following initiation of therapy. Bronchial alveolar lavages and other respiratory fluids are being evaluated from patients with documented chronic and acute Aspergillus infections before and after initiation of antifungal therapy. An Aspergillus PCR and a novel expression profiling method is being used to detect the presence of A. fumigatus; and real-time PCR assays using molecular beacon technology is being applied to recognize well-defined resistance markers in cyp51A gene. This work will advance our understanding of the importance of triazole resistance in the management of patients with chronic Aspergillus and allergic disease requiring prolonged antifungal therapy. This work is supported by NIH/NIAID grant 1R21AI103636.
Drug discovery against multidrug resistant bacteria causing both systemic and wound Infections
Center of Excellence in Translational research (CETR) to develop therapeutic countermeasures to high-threat bacterial agents.An epidemic of multidrug-resistant (MDR) bacterial infections plagues global and U.S. healthcare, and with few new antibiotics making it to market from a diminished pipeline, there is an unmet medical need for new therapeutics to treat drug-resistant infections. Furthermore, effective therapies are urgently needed to address ongoing public health and biosecurity concerns that high-threat select agent bacteria can be engineered to become resistant to currently available antibiotics. The goal of the Rutgers CETR is to help develop a new generation of antibiotics against known MDR bacteria. The CETR is a collaborative public-private partnership involving senior investigators at Rutgers University, Rockefeller University and Cubist Pharmaceuticals. It will serve to jump-start the discovery of novel antibiotics by joining together highly creative senior researchers and providing critical core resources to turn highly promising early concept molecules into potential therapeutics suitable for clinical evaluation. The CETR will examine known, well established, and novel therapeutic targets, and it will facilitate target validation, chemical lead identification, structure-activity relationship analysis, pharmacokinetics and therapeutic efficacy in animal models. The goal is to develop optimized chemical lead compounds that are suitable antibiotic candidates for preclinical evaluation. Critical factors for success include the strength of highly accomplished project and core leaders, a comprehensive and highly integrated infrastructure of support cores for lead compound optimization and validation, and access to the Rutgers Regional Biocontainment Laboratory (RBL), an NIH designated national research center for high-threat agents. Finally, the CETR leadership group is highly experienced in executing product-oriented translational research and a Scientific Advisory Committee comprised of veteran members of PhRMA and academia will guide them. This program is supported by NIH/NIAID grant 1U19AI109713.
Evaluation of carbohydrate-derived fulvic acid (CHD-FA) in preventing the development of multidrug resistant bacterial and fungal infections in traumatic wounds. The objective of this study is to demonstrate the potent antimicrobial properties of carbohydrate-derived fulvic acid (CHD-FA) against a broad collection of drug-sensitive and multi-drug resistant bacterial and fungal pathogens commonly associated with wound infections, and assess the relative efficacy of CHD-FA against induced wound infections in in vivo animal models. CHD-FA possess broad-spectrum antimicrobial behavior and is highly active on a wide array of multi drug resistant Gram positive and Gram negative bacteria, as well as common fungal pathogens. CHD-FA also shows anti-inflammatory properties and has properties that are ideal for field deployment as a broad-spectrum topical antimicrobial. Given its novel mechanism of action, activity against MDR bacteria and fungi, and anti-inflammatory activity, the early use of CHD-FA may present an advantage over existing agents to prevent serious infections following traumatic injuries including skin/soft tissue and burns. This work is supported by Department of Defense grant (CDMRP) DM110303.
Animal models of infection. We are actively engaged in developing and running BSL2/BSL3 small animal infection models for bacterial, fungal and viral pathogens.
Provide small animal infection models for ESKAPE, TB and select agent bacterial pathogens to evaluate lead compounds. The models include skin and soft tissue infection (SSTI) models (ESKAPE pathogens), pneumonia (ESKAPE and Select Agents) and systemic bacteremia (ESKAPE) models. For M.tb, acute and chronic infection models are used to assess leads at different stages of M.tb infection in rodents and rabbits. We perform measurements of host response and bacterial burden analyses at both the molecular and cellular levels. Assays include wound closure measurements, histopathologic assessment of wound healing, host wound healing pathway RNA profiling, reduction of bacterial burden and in vivo imaging. All the services provided can be performed under high-level BSL3 biocontainment in the Rutgers RBL, which served as the Small Animal Core for the Northeast Biodefense Center’s (NIH RCE Region II) for the past 12 years. An important part of the ongoing RBL function is to maintain small animal models of select agents, including murine and other small animal models of infection with Mycobacterium tuberculosis (MDR/XDR- TB), Bacillus anthracis, Yersinia pestis, Francisella tularensis, Burkholderia spp., avian and pandemic flu. In the past eight years, our group has logged >1.5 million animal days of BSL3 infection agents, including >650,000 with tier 1 select agents. We have run more than 20 vaccine studies with these agents during this period.
Zhao Y, Prideaux B, Nagasaki Y, Lee MH, Chen PY, Blanc L, Ho H, Clancy CJ, Nguyen MH, Dartois V, Perlin DS (2017) Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model. Antimicrob Agents Chemother 61. PMI: 28739797
Kordalewska M, Zhao Y, Lockhart SR, Chowdhary A, Berrio I, Perlin DS (2017) Rapid and Accurate Molecular Identification of the Emerging Multidrug-Resistant Pathogen Candida auris. J Clin Microbiol 55: 2445-2452. PMI: 28539346
Jimenez-Ortigosa C, Moore C, Denning DW, Perlin DS (2017) Emergence of Echinocandin Resistance Due to a Point Mutation in the fks1 Gene of Aspergillus fumigatus in a Patient with Chronic Pulmonary Aspergillosis. Antimicrob Agents Chemother 61. PMI: 28923871
Healey KR, Nagasaki Y, Zimmerman M, Kordalewska M, Park S, Zhao Y, Perlin DS (2017) The gastrointestinal tract is a major source of echinocandin drug resistance in a murine model of Candida glabrata colonization and systemic dissemination. Antimicrob Agents Chemother. PMI: 28971865
Zhao Y, Nagasaki Y, Kordalewska M, Press EG, Shields RK, Nguyen MH, Clancy CJ, Perlin DS (2016) Rapid Detection of FKS-Associated Echinocandin Resistance in Candida glabrata. Antimicrob Agents Chemother 60: 6573-6577. PMI: 27550360
Healey KR, Zhao Y, Perez WB, Lockhart SR, Sobel JD, Farmakiotis D, Kontoyiannis DP, Sanglard D, Taj-Aldeen SJ, Alexander BD, Jimenez-Ortigosa C, Shor E, Perlin DS (2016) Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun 7: 11128. PMI: 27020939
Krel M, Petraitis V, Petraitiene R, Jain MR, Zhao Y, Li H, Walsh TJ, Perlin DS (2014) Host biomarkers of invasive pulmonary aspergillosis to monitor therapeutic response. Antimicrob Agents Chemother 58: 3373-3378. PMI: 24687510
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
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
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
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
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
Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS (2008) A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility. Antimicrob Agents Chemother 52: 2305-2312. PMI: 18443110
Park S, Kelly R, Kahn JN, Robles J, Hsu MJ, Register E, Li W, Vyas V, Fan H, Abruzzo G, Flattery A, Gill C, Chrebet G, Parent SA, Kurtz M, Teppler H, Douglas CM, Perlin DS (2005) Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother 49: 3264-3273. PMI: 16048935
Nascimento AM, Goldman GH, Park S, Marras SA, Delmas G, Oza U, Lolans K, Dudley MN, Mann PA, Perlin DS (2003) Multiple resistance mechanisms among Aspergillus fumigatus mutants with high-level resistance to itraconazole. Antimicrob Agents Chemother 47: 1719-1726. PMI: 12709346
BOOKS and CHAPTERS
Perlin, D.S. 2014. Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management. Drugs. In press.
Zhao, Y. and Perlin, D.S. 2014.Use of novel tools to probe drug resistance in fungi. Springer. In press.
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.
Please follow this link to download a PDF copy of David Perlin's CV.