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Using Saccharomyces Cerevisiae for the Biosynthesis of Tetracycline Antibiotics

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Using Saccharomyces Cerevisiae for the Biosynthesis of Tetracycline Antibiotics Using Saccharomyces cerevisiae for the Biosynthesis of Tetracycline Antibiotics Ehud Herbst Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Ehud Herbst All rights reserved ABSTRACT Using Saccharomyces cerevisiae for the biosynthesis of tetracycline antibiotics Ehud Herbst Developing treatments for antibiotic resistant bacterial infections is among the most urgent public health challenges worldwide. Tetracyclines are one of the most important classes of antibiotics, but like other antibiotics classes, have fallen prey to antibiotic resistance. Key small changes in the tetracycline structure can lead to major and distinct pharmaceutically essential improvements. Thus, the development of new synthetic capabilities has repeatedly been the enabling tool for powerful new tetracyclines that combatted tetracycline-resistance. Traditionally, tetracycline antibiotics were accessed through bacterial natural products or semisynthetic analogs derived from these products or their intermediates. More recently, total synthesis provided an additional route as well. Importantly however, key promising antibiotic candidates remained inaccessible through existing synthetic approaches. Heterologous biosynthesis is tackling the production of medicinally important and structurally intriguing natural products and their unnatural analogs in tractable hosts such as Saccharomyces cerevisiae. Recently, the heterologous biosynthesis of several tetracyclines was achieved in Streptomyces lividans through the expression of their respective biosynthetic pathways. In addition, the heterologous biosynthesis of fungal anhydrotetracyclines was shown in S. cerevisiae. This dissertation describes the use of Saccharomyces cerevisiae towards the biosynthesis of target tetracyclines that have promising prospects as antibiotics based on the established structure- activity relationship of tetracyclines but have been previously synthetically inaccessible. Chapter 1 provides an introduction to the pursuit of tetracycline antibiotics using S. cerevisiae. Following an overview of tetracycline drugs, the chapter describes the methods for making tetracyclines and their limitations in accessing the tetracycline analogs targeted in this study. The desirability of making these target analogs as well as key desired properties are then exemplified by natural products, totally synthetic and semisynthetic derivatives. The target tetracycline analogs pursued in this study are then outlined and the considerations in choosing their desired properties are discussed, as well as the reasons for employing S. cerevisiae in their synthesis. Chapter 2 describes the use of Saccharomyces cerevisiae for the final steps of tetracycline biosynthesis, setting the stage for total biosynthesis of tetracyclines in Saccharomyces cerevisiae. Chapter 3 describes the work towards biosynthesis of the target tetracycline analogs using Saccharomyces cerevisiae, utilizing successful expression optimization and gene biomining approaches. Chapter 4 describes the work towards the target tetracycline analogs from fungal anhydrotetracyclines in Saccharomyces cerevisiae. The challenge of enzyme evolution towards unnatural substrates and the complex environment of cells require metabolic engineering efforts to be performed in libraries, as it is currently impossible to predetermine which modifications will prove beneficial. Traditional methods in DNA mutagenesis and increasingly, advances in DNA synthesis, DNA assembly and genome engineering are enabling high throughput strain construction. Thus, there is a need for a general, high-throughput, versatile and readily implemented assay for the detection of target molecule biosynthesis. The development of such an assay is described in Chapter 5. The assay is demonstrated to detect tetracycline derivatives, and differentiate a producer and a nonproducer strain of the fungal anhydrotetracycline TAN-1612. The yeast three hybrid assay for metabolic engineering of tetracycline derivatives described in this chapter could be used in the next steps towards the heterologous biosynthesis of the target tetracycline analogs in S. cerevisiae and beyond. Table of Contents List of Figures……………………………………………………………………………………vii List of Schemes……………………………………………………………………………………x List of Tables……………………………………………………………………………………...xi List of Abbreviations……………………………………………………………………………xiii 1 An introduction to tetracycline biosynthesis using Saccharomyces cerevisiae ...................... 1 1.1 Chapter outline ................................................................................................................. 2 1.2 An antibiotic crisis ........................................................................................................... 2 1.3 Tetracycline antibiotics .................................................................................................... 3 1.3.1 General historical context for tetracycline antibiotics and tetracycline-resistance ....... 3 1.3.2 Tetracycline analogs – small structural changes can lead to major pharmaceutical improvements .......................................................................................................................... 3 1.3.3 A structural overview of the FDA-approved tetracyclines ........................................... 4 1.4 Making tetracycline antibiotics ........................................................................................ 8 1.4.1 Biosynthesis and semisynthesis of tetracyclines using the original microbial hosts .... 9 1.4.2 Total synthesis of tetracycline antibiotics ................................................................... 12 1.4.3 Heterologous biosynthesis and semisynthesis of tetracyclines ................................... 14 1.5 Tetracycline analogs in the 6-position ........................................................................... 17 1.5.1 Dactylocyclines – natural product 6-epiglycotetracyclines ........................................ 17 1.5.2 6-demethyl-6-deoxy-6α-aryltetracyclines – totally synthetic tetracyclines ................ 18 i 1.5.3 6-demethyl-6-deoxy-6α-methylenemercaptantetracyclines – semisynthetic tetracyclines ........................................................................................................................... 19 1.6 Design of the biosynthesis of 6-demethyl-6-epiglycotetracyclines using S. cerevisiae 21 1.6.1 Targeting 6-demethyl derivatives of 6-epiglycotetracyclines for acid stability ......... 21 1.6.2 Targeting glycoside libraries on 6-demethyl-6-epiglycotetracyclines for broad spectrum activity.................................................................................................................... 23 1.6.3 Targeting the 6-epi forms of 6-demethylglycotetracyclines for antibiotic efficacy ... 25 1.6.4 S. cerevisiae as the heterologous host of choice for 6-demethyl-6-epiglycotetracycline biosynthesis ........................................................................................................................... 26 1.7 Research progress and future goals in the biosynthesis of 6-demethyl-6- epiglycotetracyclines using S. cerevisiae .................................................................................. 29 1.7.1 Chapter 2 – Using Saccharomyces cerevisiae for the final steps of tetracycline biosynthesis ........................................................................................................................... 29 1.7.2 Chapter 3 – Towards the biosynthesis of 6-demethyl-6-epitetracyclines using S. cerevisiae ............................................................................................................................... 30 1.7.3 Chapter 4 – Towards the biosynthesis of 6-demethyl-6-epitracyclines from TAN-1612 in Saccharomyces cerevisiae ................................................................................................. 30 1.7.4 Chapter 5 – a yeast three hybrid system for the metabolic engineering of tetracycline derivatives .............................................................................................................................. 31 1.8 References ...................................................................................................................... 32 2 Using Saccharomyces cerevisiae for the final steps of tetracycline biosynthesis ................. 41 ii 2.1 Chapter outline ............................................................................................................... 42 2.2 Introduction .................................................................................................................... 42 2.3 Materials and methods ................................................................................................... 43 2.3.1 General protocol for hydroxylation/reduction assay in cell lysate ............................. 43 2.3.2 Protocol for hydroxylation/reduction assay in whole cells ......................................... 44 2.4 Results ............................................................................................................................ 45 2.4.1 6β-hydroxylation of anhydrotetracycline in S. cerevisiae .......................................... 45 2.4.2 5a(11a)-dehydrotetracycline reduction in S. cerevisiae .............................................. 50 2.5 Discussion .....................................................................................................................
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