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A Bacterial Cytological Profile (BCP) Guided Approach to Mining Bacterial Natural Products and Synthetic Compound Libraries for Antibiotic Discovery


The exponential increase in multi-drug resistant pathogens is unmet by the number of effective antibiotics to treat their infections, posing a serious threat to human global heath. To address this issue we need new sources and better tools to discovery new antibiotics. Bacterial cytological profiling (BCP) is a new tool that rapidly identifies the mechanism of action of bioactive compounds and is applicable to natural product discovery and serves as a guide to increase the hit to lead ratio among chemical library screens. This dissertation includes five chapters that explore bacterial natural products and synthetic small molecules, guided by BCP, for the discovery of new antibacterials. The first chapter introduces potential sources for novel discoveries and describes the utility of BCP, followed by three research chapters and a summary chapter.

Chapter 2 describes the diversity and antibacterial activity of bacteria cultured and isolated from four limestone caves in Carlsbad Caverns National Park (NM, USA). A genus level phylogenetic tree was generated to display the diversity of the bacteria. The antibacterial activities were characterized via bacterial cytological profiling (BCP) and the cross streak method. The biosynthetic potential of four Actinobacteria and five Bacillus sp. was investigated via genome mining for biosynthetic gene clusters.

Chapter 3 presents the discovery of novel antibiotics that inhibit DNA replication by targeting E. coli thymidylate kinase (TMK). BCP was used to identify these molecules from a synthetic small molecule library screen and to guide the structure activity relationship (SAR) studies aimed to identify compounds with improved bioactivity that also target DNA.

The final research chapter presents a study of the isolation and characterization of Streptomyces sp. bacteriophages and describes the biosynthetic arsenals of their associated hosts. Four Streptomyces sp. were isolated from soil samples and their bioactivity was determined against strains of E. coli and B. subtilis. Additionally, bacteriophages were isolated from the soil samples, their genomes were sequenced, assembled, and annotated, and their host range was described. The bacterial genomes were assessed for known phage immunity factors to further characterize the host range of each bacteriophage and elucidate their potential use for Streptomyces genetic manipulation.

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