Exploration of Chemical Biology Approaches to Facilitate the Discovery and Development of Novel Antibiotics

Abstract

Approximately 2.8 million people worldwide are infected with bacteria that are deemed resistant to clinically relevant antibiotics. This accounts for 700,000 deaths every year and represents a major public health threat that has been on the rise for the past two decades. In contrast, the pace of antibiotic discovery to treat these resistant pathogens has significantly decreased. Most antibiotics are complex natural products that were isolated from soil microorganisms during the golden era of antibiotic discovery (1940s to 1960s) employing the “Waksman platform”. After the collapse of this discovery platform, other strategies and approaches emerged, including phenotype- or target-based screenings of large synthetic compound libraries. However, these methods have not resulted in the discovery and/or development of new drugs for clinical use in over 30 years. A better understanding of the structure and function of the molecular components that constitute the bacterial system is of paramount importance to design new strategies to tackle drug-resistant pathogens. Herein, we review the traditional approaches as well as novel strategies to facilitate antibiotic discovery that are chemical biology-focused. These include the design and application of chemical probes that can undergo bioorthogonal reactions, such as copper (I)-catalyzed azide-alkyne cycloadditions (CuAAC). By specifically interacting with bacterial proteins or being incorporated in the microorganism’s metabolism, chemical probes are powerful tools in drug discovery that can help uncover new drug targets and investigate the mechanisms of action and resistance of new antibacterial leads.