Plasmids are the main mobile elements responsible for horizontal gene transfer (HGT) in microorganisms. These replicons extend the metabolic spectrum of their host cells by carrying functional genes. However, it is still unknown to what extent plasmids carry biosynthetic gene clusters (BGCs) related to the production of secondary or specialized metabolites (SMs). Here, we analyzed 9,183 microbial plasmids to unveil their potential to produce SMs, finding a large diversity of cryptic BGCs in a few varieties of prokaryotic host taxa. Some of these plasmids harbored 15 or more BGCs, and many others were exclusively dedicated to mobilizing BGCs. We found an occurrence pattern of BGCs within groups of homologous plasmids shared by a common taxon, mainly in host-associated microbes (e.g., Rhizobiales, Enterobacteriaceae members). Our results add to the knowledge of the ecological functions and potential industrial uses of plasmids and shed light on the dynamics and evolution of SMs in prokaryotes. IMPORTANCE Plasmids are mobile DNA elements that can be shared among microbial cells, and they are useful for bringing to fruition some microbial ecological traits. However, it is not known to what extent plasmids harbor genes related to the production of specialized/secondary metabolites (SMs). In microbes, these metabolites are frequently useful for defense purposes, signaling, etc. In addition, these molecules usually have biotechnological and clinical applications. Here, we analyzed the content, dynamics, and evolution of genes related to the production of SMs in >9,000 microbial plasmids. Our results confirm that some plasmids act as a reservoir of SMs. We also found that some families of biosynthetic gene clusters are exclusively present in some groups of plasmids shared among closely related microbes. Host-associated bacteria (e.g., plant and human microbes) harbor the majority of specialized metabolites encoded in plasmids. These results provide new knowledge about microbial ecological traits and might enable the discovery of novel metabolites.

• Klíčová slova
• megaplasmids, microbial ecology, plasmids, secondary metabolism,
• MeSH
• Bacteria * genetika   MeSH
• lidé MeSH
• multigenová rodina * MeSH
• plazmidy genetika   MeSH
• sekundární metabolismus genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In natural environments, antibiotics are important means of interspecies competition. At subinhibitory concentrations, they act as cues or signals inducing antibiotic production; however, our knowledge of well-documented antibiotic-based sensing systems is limited. Here, for the soil actinobacterium Streptomyces lincolnensis, we describe a fundamentally new ribosome-mediated signaling cascade that accelerates the onset of lincomycin production in response to an external ribosome-targeting antibiotic to synchronize antibiotic production within the population. The entire cascade is encoded in the lincomycin biosynthetic gene cluster (BGC) and consists of three lincomycin resistance proteins in addition to the transcriptional regulator LmbU: a lincomycin transporter (LmrA), a 23S rRNA methyltransferase (LmrB), both of which confer high resistance, and an ATP-binding cassette family F (ABCF) ATPase, LmrC, which confers only moderate resistance but is essential for antibiotic-induced signal transduction. Specifically, antibiotic sensing occurs via ribosome-mediated attenuation, which activates LmrC production in response to lincosamide, streptogramin A, or pleuromutilin antibiotics. Then, ATPase activity of the ribosome-associated LmrC triggers the transcription of lmbU and consequently the expression of lincomycin BGC. Finally, the production of LmrC is downregulated by LmrA and LmrB, which reduces the amount of ribosome-bound antibiotic and thus fine-tunes the cascade. We propose that analogous ABCF-mediated signaling systems are relatively common because many ribosome-targeting antibiotic BGCs encode an ABCF protein accompanied by additional resistance protein(s) and transcriptional regulators. Moreover, we revealed that three of the eight coproduced ABCF proteins of S. lincolnensis are clindamycin responsive, suggesting that the ABCF-mediated antibiotic signaling may be a widely utilized tool for chemical communication. IMPORTANCE Resistance proteins are perceived as mechanisms protecting bacteria from the inhibitory effect of their produced antibiotics or antibiotics from competitors. Here, we report that antibiotic resistance proteins regulate lincomycin biosynthesis in response to subinhibitory concentrations of antibiotics. In particular, we show the dual character of the ABCF ATPase LmrC, which confers antibiotic resistance and simultaneously transduces a signal from ribosome-bound antibiotics to gene expression, where the 5' untranslated sequence upstream of its encoding gene functions as a primary antibiotic sensor. ABCF-mediated antibiotic signaling can in principle function not only in the induction of antibiotic biosynthesis but also in selective gene expression in response to any small molecules targeting the 50S ribosomal subunit, including clinically important antibiotics, to mediate intercellular antibiotic signaling and stress response induction. Moreover, the resistance-regulatory function of LmrC presented here for the first time unifies functionally inconsistent ABCF family members involving antibiotic resistance proteins and translational regulators.

• Klíčová slova
• ABCF ATPase, Streptomyces, antibiotic biosynthesis, antibiotic resistance, antibiotic-mediated signaling, chemical communication, regulation of gene expression, ribosomal regulation, signal transduction, specialized metabolism,
• MeSH
• adenosintrifosfatasy metabolismus   MeSH
• antibakteriální látky biosyntéza   farmakologie   MeSH
• bakteriální léková rezistence MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• linkomycin biosyntéza   farmakologie   MeSH
• methyltransferasy MeSH
• multigenová rodina MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• regulace genové exprese u bakterií účinky léků   MeSH
• ribozomy metabolismus   MeSH
• signální transdukce MeSH
• Streptomyces metabolismus   MeSH
• transkripční faktory MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• antibakteriální látky MeSH
• bakteriální proteiny MeSH
• linkomycin MeSH
• methyltransferasy MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• rRNA (adenosine-O-2'-)methyltransferase MeSH Prohlížeč
• transkripční faktory MeSH

We report the cloning and sequence analysis of a gamma-butyrolactone autoregulator regulatory island that includes an sscR gene encoding the gamma-butyrolactone autoregulator receptor from Streptomyces scabies NBRC 12914, a plant pathogenic strain. gamma-Butyrolactone autoregulators trigger secondary metabolism, and sometimes morphological differentiation in the Gram-positive genus Streptomyces through binding to a specific autoregulator receptor. This gene cluster showed close similarity to other regulatory islands of Streptomyces origin that are responsible for the control of secondary metabolism. The recombinant SscR protein expressed in Escherichia coli prefers a gamma-butyrolactone autoregulator containing a long C-2 side chain and beta-hydroxyl group at the C-6 position. An inactivation experiment confirmed that this gamma-butyrolactone autoregulator receptor was involved in secondary metabolism but had no effects on the morphological differentiation. In the sscR-deleted mutant, the binding activity of the gamma-butyrolactone autoregulator was completely abolished, suggesting that its primary role is to detect the presence of an autoregulator in the environment. HPLC analysis of the culture broth showed that some peaks disappeared and new peaks that were not present in the broth of the wild-type strain appeared.

• MeSH
• bakteriální proteiny chemie   genetika   metabolismus   MeSH
• gama-butyrolakton metabolismus   MeSH
• klonování DNA MeSH
• molekulární sekvence - údaje MeSH
• receptory GABA-A chemie   genetika   metabolismus   MeSH
• regulace genové exprese u bakterií MeSH
• regulační geny * MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• Streptomyces chemie   genetika   metabolismus   MeSH
• umlčování genů * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-butyrolactone receptor MeSH Prohlížeč
• bakteriální proteiny MeSH
• gama-butyrolakton MeSH
• receptory GABA-A MeSH