The Antibiotic Resistome: A Guide for the Discovery of Natural Products as Antimicrobial Agents

The use of life-saving antibiotics has long been plagued by the ability of pathogenic bacteria to acquire and develop an array of antibiotic resistance mechanisms. The sum of these resistance mechanisms, the antibiotic resistome, is a formidable threat to antibiotic discovery, development, and use. The study and understanding of the molecular mechanisms in the resistome provide the basis for traditional approaches to combat resistance, including semisynthetic modification of naturally occurring antibiotic scaffolds, the development of adjuvant therapies that overcome resistance mechanisms, and the total synthesis of new antibiotics and their analogues. Using two major classes of antibiotics, the aminoglycosides and tetracyclines as case studies, we review the success and limitations of these strategies when used to combat the many forms of resistance that have emerged toward natural product-based antibiotics specifically. Furthermore, we discuss the use of the resistome as a guide for the genomics-driven discovery of novel antimicrobials, which are essential to combat the growing number of emerging pathogens that are resistant to even the newest approved therapies.