Microbial culture conditions in the laboratory, which conventionally involve the cultivation of one strain in one culture vessel, are vastly different from natural microbial environments. Even though perfectly mimicking natural microbial interactions is virtually impossible, the cocultivation of multiple microbial strains is a reasonable strategy to induce the production of secondary metabolites, which enables the discovery of new bioactive natural products. Our coculture of marine Streptomyces and Bacillus strains isolated together from an intertidal mudflat led to discover a new metabolite, dentigerumycin E (1). Dentigerumycin E was determined to be a new cyclic hexapeptide incorporating three piperazic acids, N-OH-Thr, N-OH-Gly, β-OH-Leu, and a pyran-bearing polyketide acyl chain mainly by analysis of its NMR and MS spectroscopic data. The putative PKS-NRPS biosynthetic gene cluster for dentigerumycin E was found in the Streptomyces strain, providing clear evidence that this cyclic peptide is produced by the Streptomyces strain. The absolute configuration of dentigerumycin E was established based on the advanced Marfey's method, ROESY NMR correlations, and analysis of the amino acid sequence of the ketoreductase domain in the biosynthetic gene cluster. In biological evaluation of dentigerumycin E (1) and its chemical derivatives [2-N,16-N-deoxydenteigerumycin E (2) and dentigerumycin methyl ester (3)], only dentigerumycin E exhibited antiproliferative and antimetastatic activities against human cancer cells, indicating that N-OH and carboxylic acid functional groups are essential for the biological activity.

Pseudomonas aeruginosa is an opportunistic pathogen that coordinates the production of many virulence phenotypes at high population density via quorum sensing (QS). The LuxR-type receptor RhlR plays an important role in the P. aeruginosa QS process, and there is considerable interest in the development of chemical approaches to modulate the activity of this protein. RhlR is activated by a simple, low molecular weight N-acyl L-homoserine lactone signal, N-butanoyl-L-homoserine lactone (BHL). Despite the emerging prominence of RhlR in QS pathways, there has been limited exploration of the chemical features of the BHL scaffold that are critical to its function. In the current study, we sought to systematically delineate the structure-activity relationships (SARs) driving BHL activity for the first time. A focused library of BHL analogs was designed, synthesized, and evaluated in cell-based reporter gene assays for RhlR agonism and antagonism. These investigations allowed us to define a series of SARs for BHL-type ligands and identify structural motifs critical for both activation and inhibition of the RhlR receptor. Notably, we identified agonists that have ~10-fold higher potencies in RhlR relative to BHL, are highly selective for RhlR agonism over LasR, and are active in the P. aeruginosa background. These compounds and the SARs reported herein should pave a route toward new chemical strategies to study RhlR in P. aeruginosa.

Chemical investigation of a halophilic actinomycete strain belonging to the genus Nocardiopsis inhabiting a hypersaline saltern led to the discovery of new 18-membered macrolides with nitrile functionality, borrelidins C-E (1-3), along with a previously reported borrelidin (4). The planar structures of borrelidins C-E, which are new members of the rare borrelidin class of antibiotics, were elucidated by NMR, mass, IR, and UV spectroscopic analyses. The configurations of borrelidines C-E were determined by the interpretation of ROESY NMR spectra, J-based configuration analysis, a modified Mosher's method, and CD spectroscopic analysis. Borrelidins C and D displayed inhibitory activity, particularly against the Gram-negative pathogen Salmonella enterica, and moderate cytotoxicity against the SNU638 and K562 carcinoma cell lines.

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Lydiamycin A (1) is a previously reported piperazic acid-bearing cyclic peptide from Streptomyces. The absolute configuration of lydiamycin A has not been fully determined despite the fact that multiple total syntheses have been reported. The absolute configuration of 1 was reinvestigated by the advanced Marfey’s method, chemical derivatization, and quantum-mechanics-based computational analysis, eventually resulting in a structural revision and establishment of the complete configuration. Lydiamycin A displayed weak antituberculosis activity in vitro.