Recent developments in self-resistance gene directed natural product discovery

Abstract

Covering: 2000 to 2019Natural products (NPs) are important sources of human therapeutic agents and pesticides. To prevent self-harm from bioactive NPs, some microbial producers employ self-resistance genes to protect themselves. One effective strategy is to employ a self-resistance enzyme (SRE), which is a slightly mutated version of the original metabolic enzyme, and is resistant to the toxic NP but is still functional. The presence of a SRE in a gene cluster can serve as a predictive window to the biological activity of the NPs synthesized by the pathway. In this highlight, we summarize representative examples of NP biosynthetic pathways that utilize self-resistance genes for protection. Recent discoveries based on self-resistance gene identification have helped in bridging the gap between activity-guided and genome-driven approaches for NP discovery and functional assignment.

Fig. 1

Workflow of NP discovery. (a) activity-guided NP discovery approach. (b) genome-driven NP discovery approach.

Fig. 2

Example NP DNA replication inhibitors that employ a mutated target as SRE encoded in biosynthetic gene clusters.

Fig. 3

Example NP protein biosynthesis inhibitors that employ a mutated target as SRE encoded in biosynthetic gene clusters.

Fig. 4

Example NP metabolic enzyme inhibitors that employ a mutated target as SRE encoded in biosynthetic gene clusters.

Fig. 5

NPs discovery inspired by a self-resistance gene. a. Locating the BGC of a NP with known activity. b. Rediscovering the activity of a known NP. c. Discovering NP with desired activity.