Discovery and Characterization of Natural and Synthetic Inhibitors of Biotin Biosynthesis as Potential Candidates for Antibiotic Development

Abstract

The rise of antimicrobial resistance presents a significant public health challenge, necessitating the discovery of novel therapies. Biotin biosynthesis has been recently validated as an essential target of bacterial pathogenesis and a new target for antimicrobial development. Herein, we investigate the clinical potential of synthetic and natural biotin biosynthesis inhibitors. In Chapter 2, we attempt to develop a more in vivo potent analog of MAC13772, a synthetic biotin biosynthesis inhibitor. MAC13772 was previously shown to reduce the bacterial load in Acinetobacter baumannii systemic infection murine model with a suboptimal pharmacokinetic profile. We developed several analogs with improved enzyme and whole-cell potencies, as well as longer half-life in vitro. While we were unable to identify an analog encompassing all these improved traits, this work enhanced our understanding of the limitations of the MAC13772 scaffold and can inform our future medicinal chemistry efforts. In Chapter 3, we continue investigating biotin biosynthesis inhibitors; however, our focus now shifts to nature. We discovered a unique super biosynthetic gene cluster found in Streptomyces sp. that produces four distinct natural products (NPs) and streptavidin, all targeting biotin biosynthesis. Additionally, we demonstrate that two NPs are efficacious in a multidrug-resistant Escherichia coli murine infection model. Together, these findings highlight a promising prospect for the development of biotin biosynthesis inhibitors as the next generation of broad-spectrum antibiotics.