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. 2015 Oct 16;10(10):2373-81.
doi: 10.1021/acschembio.5b00308. Epub 2015 Aug 13.

Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei

Affiliations

Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei

Christopher J Schulze et al. ACS Chem Biol. .

Abstract

Marine natural products are an important source of lead compounds against many pathogenic targets. Herein, we report the discovery of lobosamides A-C from a marine actinobacterium, Micromonospora sp., representing three new members of a small but growing family of bacterially produced polyene macrolactams. The lobosamides display growth inhibitory activity against the protozoan parasite Trypanosoma brucei (lobosamide A IC50 = 0.8 μM), the causative agent of human African trypanosomiasis (HAT). The biosynthetic gene cluster of the lobosamides was sequenced and suggests a conserved cluster organization among the 26-membered macrolactams. While determination of the relative and absolute configurations of many members of this family is lacking, the absolute configurations of the lobosamides were deduced using a combination of chemical modification, detailed spectroscopic analysis, and bioinformatics. We implemented a "molecules-to-genes-to-molecules" approach to determine the prevalence of similar clusters in other bacteria, which led to the discovery of two additional macrolactams, mirilactams A and B from Actinosynnema mirum. These additional analogs have allowed us to identify specific structure-activity relationships that contribute to the antitrypanosomal activity of this class. This approach illustrates the power of combining chemical analysis and genomics in the discovery and characterization of natural products as new lead compounds for neglected disease targets.

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Figures

Figure 1.
Figure 1.
Structures of the lobosamides and related polyene macrolactams.
Figure 2.
Figure 2.
Structure elucidation of the lobosamides. (A) Two large spin systems were identified by COSY correlations (bold bonds) and connected through a 1,3-dimethyl moiety in the polyene system using HMBC correlations (red arrows). The 26-membered macrocycle was closed through an amide linkage. (B) The configurations of the 8 alkenes were determined using NOESY correlations (black arrows) and coupling constant analysis.
Figure 3.
Figure 3.
Key ROESY correlations used in determining the relative configuration of the lobosamides. (A) Analysis of lobosamide C acetonide allowed the assignment of the hydroxyl group at C-13, the methyl group at C-8, and the relative configuration of both polyene systems. (B) The relative orientation of the distal methyl group at C-25 was determined by key ROESY correlations to both polyene chains. (C) Three dimensional structure of lobosamide C acetonide determined by DFT molecular modeling. (D) Coupling constant and ROESY analysis of lobosamide B provided the relative configuration of the hydroxyl at C-10.
Figure 4.
Figure 4.
Proposed biosynthesis of the lobosamides. (A) Organization of the lobosamide biosynthetic gene cluster (lob). (B) Biosynthesis of the 3-aminobutyrate starter unit from glutamate. (C) Module organization and proposed biosynthesis of the lobosamides.
Figure 5.
Figure 5.
Comparative analysis of related polyene BGCs. (A) Comparison of the lobosamide, mirilactam, and salinilactam BGC organization. (B) Domain organization of the polyketide synthase modules. (C) Structures of the lobosamides, mirilactams, and salinilactam.

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