Research in the Perlin Lab
Opportunistic fungal and bacterial infections. There is a global epidemic of multidrug resistant (MDR) bacterial and fungal infections that severely limit treatment choices and result in excessive morbidity and mortality. Patients with underlying immunosuppression resulting from cancer, transplantation, premature birth, burns, HIV/AIDS or other debilitating conditions are at high risk of developing such infections. Drug resistance has emerged prominently among hospital and community associated Gram negative (GN) and Gram positive (GP) pathogens, as well as certain fungal pathogens. According to a 2013 Centers for Disease Control and Prevention (CDC) antibiotic resistance threat assessment report (1), at least 2 million Americans acquire serious infections caused by antibiotic-resistant bacteria each year, resulting in 23,000 deaths and an additional $20 billion healthcare costs. Priority solutions to this global health emergency include better stewardship of existing drugs, rapid diagnostics, the development of novel drug classes, and a more comprehensive understanding of disease development and therapeutic management. The Perlin lab has been actively engaged in this pursuit for the past 20 years.
1. Drug discovery against multidrug resistant fungi and bacteria. Multidrug-resistance 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. The Perlin Lab has been involved in developing new targets and novel chemical scaffolds against high-threat fungal and bacterial pathogens. They are interested in developing both narrow- and broad-spectrum agents against high-threat multi-drug resistant bacterial and fungal pathogens commonly associated with systemic infections among immunosuppressed patients. For the past 4 years, Dr. Perlin has led an NIH designated Center of Excellence in Translational Research (CETR) that is developing a new generation of antibiotics against known MDR bacteria. The CETR, a collaborative public-private partnership involving Rutgers University, Rockefeller University and Merck Pharmaceuticals, serves 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. In addition to antibiotic development, the Perlin lab has been active in supporting drug development efforts for numerous companies engaged in antifungal drug development.
• Hover BM, Kim SH, Katz M, Charlop-Powers Z, Owen JG, Ternei MA, Maniko J, Estrela AB, Molina H, Park S, Perlin DS, Brady SF. 2018. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nat Microbiol. 3(4):415-422. doi: 10.1038/s41564-018-0110-1.
• Vila-Farres X, Chu J, Ternei MA, Lemetre C, Park S, Perlin DS, Brady SF. 2018. An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant Acinetobacter baumannii-Infected Wounds. mSphere. 2018 Jan 24;3(1). pii: e00528-17. doi: 10.1128/mSphere.00528-17.
• Vila-Farres X, Chu J, Inoyama D, Ternei MA, Lemetre C, Cohen LJ, Cho W, Reddy BV, Zebroski HA, Freundlich JS, Perlin DS, Brady SF. (2017) Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters. J Am Chem Soc. 1;139(4):1404-1407
• Zhao Y, Lee MH, Paderu P, Lee, A, Jimenez-Ortigosa C, Park S, Mansbach RS, Shaw KJ, Perlin DS. 2018. Significantly Improved Pharmacokinetics Enhances In Vivo Efficacy of APX001 against Echinocandin- and Multidrug-Resistant Candida Isolates in a Mouse Model of Invasive Candidiasis. Antimicrob Agents Chemother. 62(10). pii: e00425-18. doi: 10.1128/AAC.00425-18
• Zhao Y, Perez WB, Jiménez-Ortigosa C, Hough G, Locke JB, Ong V, Bartizal K, Perlin DS. 2016 CD101: a novel long-acting echinocandin. Cell Microbiol18(9):1308-16
• Zhao, Y., Paderu, P., Delmas, G., Park, S., Leivers, S., and Perlin, D.S. (2015). CHD-FA is a highly promising topical broad-spectrum antimicrobial for drug-resistant wound infections. Journal of The global problem of antifungal resistance: prevalence, mechanisms, and management.
Trauma and Acute Care Surgery. 79(4 Suppl 2), S121-9.
2. Drug resistance mechanisms in fungi. I have had a longstanding interest in antifungal drug resistance, which continues to be an emerging problem in medical mycology. We first reported the mechanism of clinical resistance to echinocandin class antifungal drugs in 2005 and have provided a comprehensive molecular and clinical assessment of the resistance mechanism resulting in 75 papers and reviews. Our work has been instrumental in moving the field forward and has emphasized correlations between resistance mutations, genetics, enzyme kinetic inhibition, MIC, pharmacodynamics, resistance factors and clinical outcome. This multifactorial approach was critical to the development of revised CLSI breakpoints. My lab was established (by Pfizer and Astellas) in 2008 as a Global Clinical Reference Center for molecular evaluation of echinocandin resistant strains from patients failing therapy. In this period, we have evaluated the FKS mechanism in nearly one thousand clinical isolates. We have examined the relationship between resistance, virulence, and strain lineage, and we have used PK-PD studies to understand the importance of specific mutations and potential therapeutic response. Finally, in recent years, we have helped define underlying genetic and host factors that contribute to emergence of echinocandin and multidrug resistance in Candida and Aspergillus species.
• Shor E, Schuyler J and Perlin, DS 2019. A novel, drug resistance-independent, fluorescence-based approach to measure mutation rates in microbial pathogens. mBio, in press.
• Kordalewska M, Lee A, Park S, Berrio I, Chowdhary A, Zhao Y, Perlin DS. 2018. Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. Antimicrob Agents Chemother. 62(6). pii: e00238-18. doi: 10.1128/AAC.00238-18.
• Healey KR, Nagasaki Y, Zimmerman M, Kordalewska M, Park S, Zhao Y and 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. Antimicrobial Agents and Chemotherapy. 22;61(12). pii: e01412-17. doi: 10.1128/AAC.01412-17.
• Healey KR, Perlin DS. 2018. Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata. J Fungi (Basel). 2018 Sep 1;4(3). pii: E105. doi: 10.3390/jof4030105.
• 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.
• Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A. 2017. The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis. 17(12):e383-e392. doi: 10.1016/S1473-3099(17)30316-X.
3. Rapid detection of respiratory and bloodstream infections (BSIs) and associated resistance markers. Early and appropriate antimicrobial therapy is critical to a favorable outcome for patients with respiratory and BSIs. Current diagnostic methods are inadequate and reducing the time period from specimen collection to species identification and antimicrobial susceptibility is essential for improving patient outcome. For the past decade and one-half, my group has been involved in developing next-generation nucleic acid PCR-, RNA-based, and sera protein biomarker platforms for rapid identification of bacterial and fungal pathogens, and associated drug resistance in high threat bacterial and fungal pathogens.
• Hou X, Lee A, Jiménez-Ortigosa C, Kordalewska M, Perlin DS, Zhao Y. 2018. Rapid Detection of ERG11-Associated Azole Resistance and FKS-Associated Echinocandin Resistance in Candida auris. Antimicrob Agents Chemother. 63(1). pii: e01811-18. doi: 10.1128/AAC.01811-18.
• Zhao Y, Nagasaki Y, Paderu P, Sugrue MW, Leather HL, Wingard JR, Perlin DS. 2019. Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients. Med Mycol. 2019 Jan 1;57(1):38-44. doi: 10.1093/mmy/myx164.
• Lee MH, Wiedman G, Park S, Mustaev A, Zhao Y, Perlin DS. 2018. A novel, tomographic imaging probe for rapid diagnosis of fungal keratitis. Med Mycol. 2018 56(7):796-802.
• 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. May 24. pii: JCM.00630-17. doi: 10.1128/JCM.00630-17
• 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 Chemoth60(11):6573-6577.
• Zhao Y, Paderu P, Railkar R, Douglas C, Iannone R, Shire N, Perlin DS. 2016. Blood Aspergillus RNA is a promising alternative biomarker for invasive aspergillosis. Med Mycol. 54(8):801-7. doi: 10.1093/mmy/myw043.
• Zhao Y, Garnaud C, Brenier-Pinchart MP, Thiébaut-Bertrand A, Saint-Raymond C, Camara B, Hamidfar R, Cognet O, Maubon D, Cornet M, Perlin DS. 2016. Direct Molecular diagnosis of Aspergillosis and CYP51A Profiling from respiratory samples of French patients. Front Microbiol. 7:1164.
• Denning, D.W., Park, S., Lass-Florl, C., Fraczek, M.G., Kirwan, M., Gore, R., Smith, J., Bueid, A., Moore, C.B., Bowyer, P. and Perlin, D.S. (2011) High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin. Infect Dis 52(9):1123-9.
• Zhao, Y, Park, S, Kreiswirth, BM, Ginocchio, CC and 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(7): 2067–2078.
4. Improving existing drug therapy. A key factor for successful therapy is whether a drug get to the site of infection at the desired level for efficacy. Our group, led by Dr. Nancy Zhao, has been using novel technology to image and quantify the level of drugs in life-threatening diseases resulting from intraabdominal abscesses and pulmonary lesions. This work provides insights into more effective therapy by increasing exposure levels and reducing the emergence of drug resistance resulting from suboptimal dosing. In addition to drug access, drug response is often limited factors such as an individual’s metabolism, which effect the whether a drug is present at the desired concentration over the course of therapy. Classically, therapeutic drug monitoring (TDM) has been used to assess drug levels in patients. This is often a laboratory-intensive process that can take several days. We are developing novel technology to rapidly assess drug levels of first-line antimicrobial agents in blood in real-time at the bedside.
• 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. AAC.01009-17. doi: 10.1128/AAC.01009-17.
• Healey KR, Nagasaki Y, Zimmerman M, Kordalewska M, Park S, Zhao Y and 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. Antimicrobial Agents and Chemotherapy. AAC.01412-17. doi: 10.1128/AAC.01412-17
• Wiedman GR, Zhao Y, Perlin DS. 2018. A Novel, Rapid, and Low-Volume Assay for Therapeutic Drug Monitoring of Posaconazole and Other Long-Chain Azole-Class Antifungal Drugs. mSphere. 2018 Dec 19;3(6). pii: e00623-18. Doi 10.1128/mSphere.00623-18.
• Wiedman GR, Zhao Y, Mustaev A, Ping J, Vishnubhotla R, Johnson ATC, Perlin DS. 2017. An Aptamer-Based Biosensor for the Azole Class of Antifungal Drugs. mSphere. 2017 Aug 23;2(4). pii: e00274-17. doi: 10.1128/mSphere.00274-17.
1U19AI109713 NIH/NIAID Perlin (PI) 3/01/14 – 2/28/19
Center to develop therapeutic countermeasures to high-threat bacterial agents. This program will develop and evaluate new antibacterial agents against ESKAPE and biodefense-related pathogens.
1 R01 AI138986-01 NIH/NIAID Perlin (PI) 06/01/2018 – 5/31/2023
Novel bi-specific immunoprophylactics against multi-drug resistant Gram-negative bacterial infections. The goal of this partnership grant is to develop an immunoprophylactic to Gram negative infections using the Cidara Cloudbreak platform.
1R01AI109025 NIH/NIAID Perlin (PI) 7/01/14 – 6/30/19
Critical Factors Influencing Echinocandin Resistance in Candida glabrata. The aim of this project is to determine cellular factors contributing to emergence of FKS-mediated drug resistance in Candida glabrata
Astellas Pharma US, Inc Perlin (PI) 10/01/14-1/15/19
Echinocandin Resistance Reference Center. Global reference/referral center for drug resistance related to echinocandins and azoles
CDC Perlin (PI) 9/30/16-9/29/18
A comprehensive study of multidrug resistance determinants and drivers in the major fungal pathogen Candida glabrata
CDC Perlin (PI) 9/30/17-9/29/18
Rapid identification and analysis of transmission of the emerging pathogen Candida auris
DoD 110303 CDMRP Perlin (PI) 9/30/12-4/29/17
Evaluation of Carbohydrate Derived Fulvic Acid (CHD-FA) as a topical broad-spectrum antimicrobial for drug resistant wound infections