Bringing century-old cures to the frontier of emerging antifungal resistance: A screen of natural products for anticandidal activity Pubblico

Abstract

Candida species rank as the seventh most common pathogen causing hospital-acquired infections and are the most common culprit of hospital-acquired bloodstream infections (Magill et al., 2014) . C. albicans alone accounts for 90-100% of mucosal infections (Pfaller & Diekema, 2010) . Although C. albicans is a commensal organism that normally inhabits the human gastrointestinal tract flora, it is an opportunistic fungal pathogen (Roemer & Krysan, 2014). The species is also responsible for approximately 50% of all candidiasis cases, which is associated with a crude mortality rate of 45-50% in critically ill patients, increased hospitalization length by over 14 days, and elevated medical costs by $6,000-29,000 (Gudlaugsson et al., 2003; Leroy et al., 2009; Morgan et al., 2005; Wisplinghoff et al., 2004) . Patient populations at high risk for candidiasis include cancer and immunocompromised patients (Antinori, Milazzo, Sollima, Galli, & Corbellino, 2016).

There are only four classes of drugs that are used in the clinic to treat antifungal infections (azoles, echinocandins, polyenes, and pyrimidine analogs). Echinocandins and azoles are preferred by clinicians to treat Candida infections, however, their widespread use have contributed to resistance or decreased antifungal susceptibility by Candida strains (Antinori et al., 2016) . With high rates of azole resistance and the emergence of echinocandin and multidrug resistance, there is a clear demand for new antifungal therapies (Antinori et al., 2016).

This study used an ethnobotanical approach to ultimately identify new chemical entities for antifungal drug development. By tapping into traditional herbal medicine that has persisted through centuries, we aimed to apply ancient wisdom to answer today's antimicrobial resistance crisis by screening and identifying novel antifungal compounds extracted from plants. A screening of over 300 natural products from the Quave Natural Product Library, which uniquely links each product to the traditional medical application and preparation, revealed 45 compounds that inhibit growth of C. albicans by at least 95% at a concentration of 16 μg/mL. Further analysis showed that five natural product extracts were from the leaves of the same plant species, Schinus terebinthifolia. Microbiological testing evaluated and demonstrated the growth inhibitory activity of the five extracts against both susceptible and drug-resistant C. albicans and non-albicans species. The demonstration of the bioactivity of S. terebinthifolia leaf compounds corroborates its use in traditional medicine to treat skin and soft tissue infections. These findings also identified the leaf of this plant as a promising source of antifungal molecules for drug development.

Table of Contents

CHAPTER 1: INTRODUCTION 1

Candida albicans, candidemia, and the promise of plant-derived antifungals

Project aims and research question

CHAPTER 2: LITERATURE REVIEW 6

Clinical Summary of Candida albicans and non-albicans strains

Health burden of invasive candidiasis

Current treatment of Candida infections

Health and economic impact of antimicrobial resistance

Mechanisms of antifungal resistance

Traditional medicine and plants: A source of novel antimicrobial agents

CHAPTER 3: MATERIALS AND METHODS 20

CHAPTER 4: RESULTS 25

CHAPTER 5: DISCUSSION 38

Fungistatic effects of 429, 429B, 429C, 429D, and 429E on Candida isolates

Schinus terebinthifolia in traditional medicine

Global distribution of Candida strains and the antimicrobial resistance crisis

Future directions

Conclusion

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Medicine and Surgery
Parola chiave	candida albicans
Committee Chair / Thesis Advisor	Quave, Cassandra Leah, Emory University
Committee Members	McGill, Tracy, Emory University Hickman, Meleah A, Emory University

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