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Indolizidines have long been recognized for their valuable bioactivities, their common feature being a bicyclic structure connected via a nitrogen atom. Traditionally, plants have been identified as the primary producers. However, recent discoveries have revealed that certain bacterial strains belonging to the genus of actinomycetes also possess the ability to synthesize various indolizidine-based compounds. Among these strains, Streptomyces sp. HNA39, Saccharopolyspora sp. RL78, and Streptomyces NCIB 11649 have been identified as producers of cyclizidines, characterized by their distinctive cyclopropyl moiety. Additionally, Streptomyces griseus OS-3601 synthesizes a unique class of indolizidine derivatives known as iminimycins, distinguished by their rare imine-cation structure. Protoplast fusion of a Streptomyces griseus strain with Streptomyces tenjimariensis resulted in a new indolizidine named indolizomycin. This review aims to provide an overview of known bacterial indolizidine producers, summarize current knowledge regarding the biosynthesis of cyclizidines and iminimycins, and assess their respective bioactivities. [ABSTRACT FROM AUTHOR]

Streptomyces antibiotic regulatory protein (SARP) family regulators are well-known activators of antibiotic biosynthesis in streptomycetes. The respective genes occur in various types of antibiotic gene clusters encoding, e.g., for polyketides, ribosomally and non-ribosomally synthesized peptides, or β-lactam antibiotics. We found that overexpression of the SARP-type regulator gene papR2 from Streptomyces pristinaespiralis in Streptomyces lividans leads to the activation of the silent undecylprodigiosin (Red) gene cluster. The activation happens upon the inducing function of PapR2, which takes over the regulatory role of RedD, the latter of which is the intrinsic SARP regulator of Red biosynthesis in S. lividans. Due to the broad abundance of SARP genes in different antibiotic gene clusters of various actinomycetes and the uniform activating principle of the encoded regulators, we suggest that this type of regulator is especially well suited to be used as an initiator of antibiotic biosynthesis in actinomycetes. Here, we report on a SARP-guided strategy to activate antibiotic gene clusters. As a proof of principle, we present the PapR2-driven activation of the amicetin/plicacetin gene cluster in the novel Indonesian strain isolate Streptomyces sp. SHP22-7. [ABSTRACT FROM AUTHOR]

Since the golden age of antibiotics in the 1950s and 1960s actinomycetes have been the most prolific source for bioactive natural products. However, the number of discoveries of new bioactive compounds decreases since decades. New procedures (e.g., activating strategies or innovative fermentation techniques) were developed to enhance the productivity of actinomycetes. Nevertheless, compound identification remains challenging among others due to high rediscovery rates. Rapid and cheap genome sequencing as well as the advent of bioinformatical analysis tools for biosynthetic gene cluster identification in combination with mass spectrometry-based molecular networking facilitated the tedious process of dereplication. In recent years several studies have been dedicated to accessing the biosynthetic potential of Actinomyces species, especially streptomycetes, by using integrated genomic and metabolomic screening in order to boost the discovery rate of new antibiotics. This review aims to present the various possible applications of this approach as well as the newly discovered molecules, covering studies between 2014 and 2021. Finally, the effectiveness of this approach with regard to find new bioactive agents from actinomycetes will be evaluated. [ABSTRACT FROM AUTHOR]

Indonesia is one of the most biodiverse countries in the world and a promising resource for novel natural compound producers. Actinomycetes produce about two thirds of all clinically used antibiotics. Thus, exploiting Indonesia's microbial diversity for actinomycetes may lead to the discovery of novel antibiotics. A total of 422 actinomycete strains were isolated from three different unique areas in Indonesia and tested for their antimicrobial activity. Nine potent bioactive strains were prioritized for further drug screening approaches. The nine strains were cultivated in different solid and liquid media, and a combination of genome mining analysis and mass spectrometry (MS)-based molecular networking was employed to identify potential novel compounds. By correlating secondary metabolite gene cluster data with MS-based molecular networking results, we identified several gene cluster-encoded biosynthetic products from the nine strains, including naphthyridinomycin, amicetin, echinomycin, tirandamycin, antimycin, and desferrioxamine B. Moreover, 16 putative ion clusters and numerous gene clusters were detected that could not be associated with any known compound, indicating that the strains can produce novel secondary metabolites. Our results demonstrate that sampling of actinomycetes from unique and biodiversity-rich habitats, such as Indonesia, along with a combination of gene cluster networking and molecular networking approaches, accelerates natural product identification. [ABSTRACT FROM AUTHOR]

Objectives: Atrioventricular (AV) conduction disturbances are still common following transcatheter aortic valve replacement (TAVR). The study evaluates the feasibility and clinical effect of self-expanding (SE)-TAVR employing an optimized cusp-overlay technique (COT) at 1 year in a German all-comers population., Methods: We analyzed 1-year clinical outcomes in patients who received a SE valve employing the optimized COT. Consecutive patients who underwent SE-TAVR (EvolutR, EvolutPRO) after introduction of the COT as the default implantation technique in 2020 were included (n = 101). Consecutive TAVR patients from the same operators using the conventional implantation technique (CIT) served as the control group (n = 116)., Results: The COT was successfully performed in more than 80% of the patients in the COT group. (81.2%, n = 82/101). At discharge, no difference regarding AV block of at least II (CIT 19.47% vs COT 21%; P = .86) and permanent pacemaker (PPM) implantation (CIT 17.5% vs COT 19%; P = .73) was observed between the cohorts. New left bundle branch block (LBBB) was significantly less frequent in the COT group (CIT 40.71% vs COT 26%; P = .029). Paravalvular leakage (PVL) greater than I° was reduced in the COT cohort (CIT 8.62% vs COT 0.99%; P = .012). There was no significant difference in mortality (CIT 18.27% vs COT 13.83%; P = .44), stroke (CIT 9.62% vs COT 15.96%; P = .16) or cardiovascular rehospitalization after 1 year (CIT 25.96% vs 24.47%; P = .92) between the groups., Conclusions: Implementation of COT-TAVR was feasible and safe, and it resulted in an improvement of TAVR outcomes regarding PVL greater than I° and new onset LBBB. However, with respect to PPM, no difference was observed 1-year post-TAVR.

Streptomyces sp. strain I6 is a novel strain isolated from an Indonesian mangrove sediment sample. Bioinformatic analysis of the genome sequence of Streptomyces sp. I6 revealed 23 biosynthetic gene clusters. One of them encodes the synthesis of a putative phosphonate secondary metabolite, a class of underexplored natural compounds with great pharmaceutical potential.