The Perlin lab is interested in drug discovery against multidrug resistant bacterial infections, mechanisms of antifungal drug resistance, studies of drug action at sites of infection, rapid detection of drug resistant bloodstream and respiratory pathogens in high-risk patients, and the application of small animal models for high-threat pathogens.
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 Pharmaceutical partners like Merck. It 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. The CETR examines 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 preclinical development candidates. 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 is guided by a Scientific Advisory Committee comprised of veteran members of Pharma and academia.
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) and other agents 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.
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 genomic structure, novel genes/pathways are being profiled. 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 the National Aspergillosis Center, Manchester, UK (Dr. Denning). We have characterized a wide array of mutations in the Cyp51A gene, which confers differential resistance to itraconazole, voriconazole, posaconazole and isavuconazole. 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.
Furthermore, to better understand the relationship between drug exposure and emergence of antifungal drug resistance, we have developed methodologies to quantitatively assess drug burdens in intraabdominal abscesses and pulmonary lesions. In addition, we are examining natural reservoirs, such as the GI tract, as major sources for resistance development. Our objective is to assess how drug exposure in different environments may promote the development of drug resistance. This work is being conduct in partnership with the University of Pittsburgh Medical Center (Drs. Clancy and Nguyen), Pharma and biotech drug developers.
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 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 exploring pathogen and host-based biomarkers to assess therapeutic management of disease. 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.
Finally, we have adapted aptamer technology to develop novel molecules and devices that can be used for real-time therapeutic monitoring of antifungal drugs in patients.
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, ncluding 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 >1.7 million animal days of BSL3 infection agents, including >700,000 with tier 1 select agents.
Zhao Y, Nagasaki Y, Paderu P, Sugrue MW, Leather HL, Wingard JR, Perlin DS (2018) Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients. Med Mycol. PMI: 29370415
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. PMI: 30012766
Yang F, Zhang L, Wakabayashi H, Myers J, Jiang Y, Cao Y, Jimenez-Ortigosa C, Perlin DS, Rustchenko E (2018) Correction for Yang et al., “Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling”. Antimicrob Agents Chemother 62. PMI: 29588355
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 3. PMI: 29404414
Vickers CF, Silva APG, Chakraborty A, Fernandez P, Kurepina N, Saville C, Naranjo Y, Pons M, Schnettger LS, Gutierrez MG, Park S, Kreiswith BN, Perlin DS, Thomas EJ, Cavet JS, Tabernero L (2018) Structure-Based Design of MptpB Inhibitors That Reduce Multidrug-Resistant Mycobacterium tuberculosis Survival and Infection Burden in Vivo. J Med Chem. PMI: 30153005
Taj-Aldeen SJ, Salah H, Perez WB, Almaslamani M, Motyl M, AbdulWahab A, Healey KR, Perlin DS (2018) Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar. Antimicrob Agents Chemother 62. PMI: 29941644
Suwunnakorn S, Wakabayashi H, Kordalewska M, Perlin DS, Rustchenko E (2018) FKS2 and FKS3 Genes of Opportunistic Human Pathogen Candida albicans Influence Echinocandin Susceptibility. Antimicrob Agents Chemother 62. PMI: 29358288
Singh A, Healey KR, Yadav P, Upadhyaya G, Sachdeva N, Sarma S, Kumar A, Tarai B, Perlin DS, Chowdhary A (2018) Absence of Azole or Echinocandin Resistance in Candida glabrata Isolates in India despite Background Prevalence of Strains with Defects in the DNA Mismatch Repair Pathway. Antimicrob Agents Chemother 62. PMI: 29610199
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. PMI: 29632013
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: 415-422. PMI: 29434326
Healey KR, Kordalewska M, Jimenez Ortigosa C, Singh A, Berrio I, Chowdhary A, Perlin DS (2018) Limited ERG11 mutations identified in isolates of Candida auris directly contribute to reduced azole susceptibility. Antimicrob Agents Chemother. PMI: 30082281
Chowdhary A, Prakash A, Sharma C, Kordalewska M, Kumar A, Sarma S, Tarai B, Singh A, Upadhyaya G, Upadhyay S, Yadav P, Singh PK, Khillan V, Sachdeva N, Perlin DS, Meis JF (2018) A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother 73: 891-899. PMI: 29325167
Byun SA, Won EJ, Kim MN, Lee WG, Lee K, Lee HS, Uh Y, Healey KR, Perlin DS, Choi MJ, Kim SH, Shin JH (2018) Multilocus Sequence Typing (MLST) Genotypes of Candida glabrata Bloodstream Isolates in Korea: Association With Antifungal Resistance, Mutations in Mismatch Repair Gene (Msh2), and Clinical Outcomes. Front Microbiol 9: 1523. PMI: 30057573
Break TJ, Desai JV, Healey KR, Natarajan M, Ferre EMN, Henderson C, Zelazny A, Siebenlist U, Yates CM, Cohen OJ, Schotzinger RJ, Perlin DS, Garvey EP, Lionakis MS (2018) VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice. J Antimicrob Chemother 73: 2089-2094. PMI: 29788070
Berrio I, Maldonado N, De Bedout C, Arango K, Cano LE, Valencia Y, Jimenez-Ortigosa C, Perlin DS, Gomez BL, Robledo C, Robledo J, Grupo G (2018) Comparative study of Candida spp. isolates: Identification and echinocandin susceptibility in isolates obtained from blood cultures in 15 hospitals in Medellin, Colombia. J Glob Antimicrob Resist 13: 254-260. PMI: 29183771
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