Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei.
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.
Department of Chemistry and Biochemistry, University of California Santa Cruz , Santa Cruz, California 95064, United States.
Christopher J
CJ
Schulze
Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California San Francisco , San Francisco, California 94158, United States.
Mohamed S
MS
Donia
Skaggs School of Pharmacy, University of California San Diego , San Diego, California 92093, United States.
Jair L
JL
Siqueira-Neto
Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States.
Debalina
D
Ray
Department of Chemistry and Biochemistry, University of California Santa Cruz , Santa Cruz, California 95064, United States.
Jevgenij A
JA
Raskatov
Department of Biomolecular Engineering, University of California Santa Cruz , Santa Cruz, California 95064, United States.
Richard E
RE
Green
Skaggs School of Pharmacy, University of California San Diego , San Diego, California 92093, United States.
James H
JH
McKerrow
Department of Bioengineering and Therapeutic Sciences and the California Institute for Quantitative Biosciences, University of California San Francisco , San Francisco, California 94158, United States.
Michael A
MA
Fischbach
Department of Chemistry and Biochemistry, University of California Santa Cruz , Santa Cruz, California 95064, United States.
Roger G
RG
Linington
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D005810:Multigene Family; D011090:Polyenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D000981:Antiprotozoal Agents; D007769:Lactams; D011090:Polyenes