Lysohexaenetides A and B, linear lipopeptides from Lysobacter sp. DSM 3655 identified by heterologous expression in Streptomyces / 中国天然药物

Lysobacter harbors a plethora of cryptic biosynthetic gene clusters (BGCs), albeit only a limited number have been analyzed to date. In this study, we described the activation of a cryptic polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) gene cluster (lsh) in Lysobacter sp. DSM 3655 through promoter engineering and heterologous expression in Streptomyces sp. S001. As a result of this methodology, we were able to isolate two novel linear lipopeptides, lysohexaenetides A (1) and B (2), from the recombinant strain S001-lsh. Furthermore, we proposed the biosynthetic pathway for lysohexaenetides and identified LshA as another example of entirely iterative bacterial PKSs. This study highlights the potential of heterologous expression systems in uncovering cryptic biosynthetic pathways in Lysobacter genomes, particularly in the absence of genetic manipulation tools.

Effect of Bacillus subtilis PB6, a natural probiotic on colon mucosal inflammation and plasma cytokines levels in inflammatory bowel disease.

The pathophysiology of inflammatory bowel disease (IBD) involves the production of diverse lipid mediators, namely eicosanoid, lysophospholipids, and platelet-activating factor, in which phospholipase A2 (PLA2) is the key enzyme. Thus, it has been postulated that control of lipid mediators production by inhibition of PLA2 would be useful for the treatment of IBD. This hypothesis has been tested in the present study by examining the therapeutic effect of a novel natural probitic Bacillus subtilis PB6 (ATCC- PTA 6737). B. subtilis PB6 is found to secrete surfactins (cyclic lipopeptides) which have anti-bacterial potential. These surfactins inhibit PLA2, a rate-limiting enzyme involved in the arachidonic acid associated inflammatory pathway and could downregulate the inflammatory response by regulating the eicosanoid and cytokine pathways. With this concept, an experimental animal trial has been conducted in a rat model of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. The oral administration of PB6 suppresses the colitis as measured by mortality rate, changes in the weight gain, colon morphology and the levels of plasma cytokines. The animals treated orally with PB6 at 1.5 x 10(8) CFU/kg thrice daily from day 4 to 10 significantly improve gross pathology of the colon and regain the colon weight to normal (p < 0.05), compared to TNBS-induced positive control. The plasma levels of pro-inflammatory cytokines (TNF-alpha, 1L-1beta, IL-6 and IFN-gamma) are also significantly lowered (p < 0.05) and anti-inflammatory cytokine (IL-I0 and TGF-beta) significantly (p < 0.05) increased after the oral administration of PB6 on day 11. The present study supports the concept that PB6 inhibits PLA2 by the secreting surfactins. In a clinical investigation, it is found to be well tolerated by all the healthy volunteers.