Antibiotic export: transporters involved in the final step of natural product production

In the fight against antimicrobial resistance (AMR), antibiotic biosynthetic gene clusters are constantly being discovered. These clusters often include genes for membrane transporters that are involved in the export of the produced natural product during biosynthesis and/or subsequent resistance through active efflux. Despite transporter genes being integral parts of these clusters, study of the function of antibiotic export in natural producers such as Streptomyces spp. remains underexplored, in many cases lagging far behind our understanding of the biosynthetic enzymes. More efficient release of antibiotics by producing cells has potential benefits to industrial biotechnology and understanding the relationships between exporters in natural producers and resistance-associated efflux pumps in pathogens can inform our efforts to understand how AMR spreads. Herein we compile and critically assess the literature on the identification and characterization of antibiotic exporters and their contribution to production in natural antibiotic producers. We evaluate examples of how this knowledge could be used in biotechnology to increase yields of the final product or modulate its chemical nature. Finally, we consider the evidence that natural exporters form a reservoir of protein functions that could be hijacked by pathogens as efflux pumps and emphasize the need for much greater understanding of these exporters to fully exploit their potential for applications around human health.