TY - JOUR
T1 - Genome-Directed Lead Discovery
T2 - Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei
AU - Schulze, Christopher J.
AU - Donia, Mohamed S.
AU - Siqueira-Neto, Jair L.
AU - Ray, Debalina
AU - Raskatov, Jevgenij A.
AU - Green, Richard E.
AU - McKerrow, James H.
AU - Fischbach, Michael A.
AU - Linington, Roger G.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/10/16
Y1 - 2015/10/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84944727204&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84944727204&partnerID=8YFLogxK
U2 - 10.1021/acschembio.5b00308
DO - 10.1021/acschembio.5b00308
M3 - Article
C2 - 26270237
AN - SCOPUS:84944727204
SN - 1554-8929
VL - 10
SP - 2373
EP - 2381
JO - ACS chemical biology
JF - ACS chemical biology
IS - 10
ER -