Genetic Manipulation of an Aminotransferase Family Gene dtlA Activates Youssoufenes in Marine-Derived Streptomyces youssoufiensis

Abstract

Disruption of an aminotransferase family gene dtlA activated the production of a novel dimeric benzoic polyene acids (BPAs), named youssoufene A1 (1), along with four new (2−5, youssoufenes B1−B4) and a known (6) monomeric BPA in the marine-derived Streptomyces youssouf iensis OUC6819. The structures of 1−5 were elucidated by extensive spectroscopic and computational approaches. Youssoufene A1 (1) exhibited notably increased growth inhibition (MIC = 12.5 μg/mL) against multidrug resistant Enterococcus faecalis compared to monomeric structures (2−6).

An Unusual Type II Polyketide Synthase System Involved in Cinnamoyl Lipid Biosynthesis

“…Cinnamoyl lipid (CL) containing compounds, featuring with an ortho ‐substituted cinnamoyl group, constitute a small family of natural products. Up to now, only a handful of CL containing compounds have been reported, such as youssoufenes ( 1 – 5 ), [1] serpentene ( 6 ), [2] diacidene, [3] lahorenoic acids, [4] and cinnamoyl‐containing nonribosomal peptides (CCNPs) (kitacinnamycins, [5] skyllamycins, [6] et al.) (Figures 1 A, S1).…”

“…(Figures 1 A, S1). Notably, CL containing compounds display a broad range of physiological activities, including but not limited to antiangiogenic, [7] antitumor, [5] antibacterial, [1] antifungal, [8] antituberculosis, [9, 10] and enzyme inhibitor [11, 12] . For example, atratumycin displays potent antituberculosis activity, [10] skyllamycin A is a potent inhibitor of the platelet‐derived growth factor (PDGF) signaling pathway, [6] and serpentemycin A possesses a strong inhibitory activity against glycosyltransferase [11]…”

“…The CL moiety was proposed to be assembled by a repeating cycle of condensation, reduction, dehydration, isomerization and then cyclization, to give the required product (Figure 1 B). Identification of the biosynthetic gene clusters (BGCs) of CLs and CCNPs indicated that the CL moiety is possibly derived from a type II polyketide synthase (PKS) system [1, 5, 6, 9, 10, 13, 14] . However, unlike the type II aromatic, [15] highly reducing (HR), [16] and acyl polyene (APE) [17] PKSs, CL PKSs not only harbor acyl carrier protein (ACP), ketosynthase (KS), ketoreductase (KR), and dehydratase (DH) (absent in some cases [9] ) domains, but also an isomerase (ISO).…”

“…Previously, we discovered several “cryptic” CL compounds youssoufenes A1 and B1–B4 by inactivation of an aminotransferase family gene dtlA in Streptomyces youssoufiensis OUC6819 [1] . The youssoufene BGC was identified by heterologous expression of ysfA ‐ K in S. coelicolor M1146 [1] .…”

“…Cinnamoyl lipid (CL) containing compounds, featuring with an ortho-substituted cinnamoyl group, constitute a small family of natural products. Up to now, only a handful of CL containing compounds have been reported, such as youssoufenes (1-5), [1] serpentene (6), [2] diacidene, [3] lahorenoic acids, [4] and cinnamoyl-containing nonribosomal peptides (CCNPs) (kitacinnamycins, [5] skyllamycins, [6] et al) (Figures 1 A, S1). Notably, CL containing compounds display a broad range of physiological activities, including but not limited to antiangiogenic, [7] antitumor, [5] antibacterial, [1] antifungal, [8] antituberculosis, [9,10] and enzyme inhibitor.…”