Yanan Zhao, M.D., Ph.D., is an Assistant Member at the Center for Discovery and Innovation
Dr. Zhao’s research has focused on preclinical studies of antifungal and antimicrobial agents, including efficacy evaluation and drug exposure measurement at the site of infection. She also devotes her efforts to developing rapid molecular diagnostics for clinically important fungal infections and associated drug resistance.
Antifungal penetration at the site of infection
One of her research interests is to study drug penetration of different antifungal agents at the site of infection, using small animal models, MALDI mass spectrometry imaging, and laser-capture microdissection (LCM) directed LC-MS/MS quantification. Invasive fungal infections remain a significant cause of morbidity and mortality worldwide. One important factor contributing to the relative ineffectiveness of existing antifungal drugs is insufficient drug exposure at the site of infection. Despite the importance of this aspect of antifungal therapy, there is a generally lack a full appreciation of how antifungal drugs distribute, penetrate and interact with their target organisms in different tissue subcompartments. A better understanding of drug distribution will be critical to guide appropriate use of currently available antifungal drugs, as well as to aid in the development of new agents. Thus far, Dr. Zhao has successfully applied the new platform (Figure 1) to unravel drug penetration patterns for a few first-line antifungal agents such as micafungin, rezafungin, and isavuconazole, in animal models recapitulating different forms of fungal infections in humans. More broadly, she believes that these types of studies are relevant to a wide range of infectious and noninfectious disease pathologies (e.g. tumors) that require effective drug exposure for clinical response.
Rapid molecular diagnostics for invasive fungal infections and antifungal resistance
It is estimated that more than 1 billion people throughout the world have fungal infections, with 1.7 million deaths a year from serious fungal infections. Yet, rapidly and accurately diagnosing fungal infections are challenging. The current phenotypic and biochemical identification methods are not only time consuming but, in many instances, insensitive to the detection of fungal pathogens. Further, in vitro susceptibility assays are not routinely performed in clinical laboratories, which prevents effective treatment and adds to the development of antifungal resistance.
To meet the increasing demand for novel diagnosis for fungal infection and antifungal drug resistance, she has worked up multiple nucleic acid amplification based molecular beacon platforms for rapid identification of important fungal pathogens such as Aspergillus fumigatus, Exserohilum rostratum, Candida glabrata, Candida auris, etc. More recently, she has developed a novel molecular diagnostic platform to identify clinically important antifungal resistance in C. glabrata and C. auris (Figure 2). These resistance diagnostic assays are rapid (< 3h from sample preparation to results), highly accurate, and easy to perform. They have the potential to overcome the deficiencies of existing MIC-based assays to identify clinically important antifungal resistance, therefore, hold the promise to be surrogate diagnostic methods to better direct antifungal therapy.
Hou X, Lee A, Jiménez-Ortigosa C, Kordalewska M, Perlin DS, Zhao Y. Rapid Detection of ERG11-Associated Azole Resistance and FKS-Associated Echinocandin Resistance in Candida auris. Antimicrobial agents and chemotherapy. 2019; 63(1).
Zhao Y, Nagasaki Y, Paderu P, Sugrue MW, Leather HL, Wingard JR, Perlin DS. Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients. Medical mycology. 2019; 57(1):38-44.
Wiedman GR, Zhao Y, Perlin DS. A Novel, Rapid, and Low-Volume Assay for Therapeutic Drug Monitoring of Posaconazole and Other Long-Chain Azole-Class Antifungal Drugs. mSphere. 2018; 3(6).
Zhao Y, Lee MH, Paderu P, Lee A, Jimenez-Ortigosa C, Park S, Mansbach RS, Shaw KJ, Perlin DS. Significantly Improved Pharmacokinetics Enhances In Vivo Efficacy of APX001 against Echinocandin- and Multidrug-Resistant Candida Isolates in a Mouse Model of Invasive Candidiasis. Antimicrobial agents and chemotherapy. 2018; 62(10).
Hou X, Xiao M, Wang H, Yu SY, Zhang G, Zhao Y, Xu YC. Profiling of PDR1 and MSH2 in Candida glabrata Bloodstream Isolates from a Multicenter Study in China. Antimicrobial agents and chemotherapy. 2018; 62(6).
Kordalewska M, Lee A, Park S, Berrio I, Chowdhary A, Zhao Y, Perlin DS. Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. Antimicrobial agents and chemotherapy. 2018; 62(6).
Lee MH, Wiedman G, Park S, Mustaev A, Zhao Y, Perlin DS. A novel, tomographic imaging probe for rapid diagnosis of fungal keratitis. Medical mycology. 2018; 56(7):796-802.
Zhao Y, Prideaux B, Nagasaki Y, Lee MH, Chen PY, Blanc L, Ho H, Clancy CJ, Nguyen MH, Dartois V, Perlin DS. Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model. Antimicrobial agents and chemotherapy. 2017; 61(10).
Healey KR, Nagasaki Y, Zimmerman M, Kordalewska M, Park S, Zhao Y, Perlin DS. 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. 2017; 61(12).
Zhao Y, Nagasaki Y, Kordalewska M, Press EG, Shields RK, Nguyen MH, Clancy CJ, Perlin DS. Rapid Detection of FKS-Associated Echinocandin Resistance in Candida glabrata. Antimicrobial agents and chemotherapy. 2016; 60(11):6573-6577.