The human microbiome is a source of therapeutic drug targets

• Microbial symbiotes significantly impact therapeutic chemistry.
• Specific enzyme targets in the microbiota can be potently and selectively disrupted.
• Inhibiting such target enzymes should be nonlethal to the microbiota.
• Modulating the human microbiome may improve drug efficacy and safety.

It was appreciated early in drug discovery that the microbiota play an important role in the efficacy of therapeutic compounds. Indeed, the first antibiotic sulfa drugs were shown in the 1940s to be transformed by the bacteria that encode what we now call the intestinal microbiome. Here we briefly review the roles symbiotic bacteria play in the chemistry of human health, and we focus on the emerging appreciation that specific enzyme targets expressed by microbial symbiotes can be selectively disrupted to achieve clinical outcomes. We conclude that components of the microbiome should be considered ‘druggable targets,’ and we suggest that our rapidly evolving understanding of the chemical biology of mammalian–microbial symbiosis will translate into improved human health.