Control of Specialized Metabolism by Signaling and Transcriptional Regulation: Opportunities for New Platforms for Drug Discovery?

Daniel-Ivad, Martin; Pimentel‐Elardo, Sheila Marie; Nodwell, Justin R.

doi:10.1146/annurev-micro-022618-042458

Cited by 27 publications

(21 citation statements)

References 123 publications

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“…It is reasonable to assume that different biosynthetic gene clusters might be co-regulated and common regulatory patterns exist in different clusters [45,46]. It is important to understand the complex regulation of secondary metabolites in bacteria, especially in Streptomyces [47,48]. It has been long known that most of the gene clusters in Streptomyces are silent under normal laboratory conditions [49,50].…”

Section: Discussionmentioning

confidence: 99%

Transcription-factor centric genome mining strategy for discovery of diverse unprecedented RiPP gene clusters

Zhu

Zheng

2018

Preprint

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly emerging group of natural products with diverse biological activity. Most of their biosynthetic mechanisms are well studied and the "genome mining" strategy based on homology has led to the unearthing of many new ribosomal natural products, including lantipeptides, lasso peptides, cyanobactins. These precursor-centric or biosynthetic protein-centric genome mining strategies have encouraged the discovery of RiPPs natural products. However, a limitation of these strategies is that the newly identified natural products are similar to the known products and novel families of RiPP pathways were overlooked by these strategies. In this work, we applied a transcription-factor centric genome mining strategy and diverse unique crosslinked RiPP gene clusters were predicted in several sequenced microorganisms. Our research could significantly expand the category of biosynthetic pathways of RiPP natural products and predict new resources for novel RiPPs. 2

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Section: Discussionmentioning

confidence: 99%

Transcription-factor centric genome mining strategy for discovery of diverse unprecedented RiPP gene clusters

Zhu

Zheng

2018

Preprint

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“…Inspired by recent work on phylogenetic analysis of cluster-associated StrR-and LuxR-related regulators 22 , we performed a phylogenetic analysis of TCSs from actinomycetes. To this end, we retrieved response regulators and sensory kinases associated with characterized actinobacterial gene clusters from the MiBIG database 23 , well-characterized TCSs from Streptomyces coelicolor 24,25 and the response regulators and sensory kinases identified in the N. gerenzanensis genome 18 (Fig. 8).…”

Section: Dbv6 and Dbv22 Are Unrelated To Other Tcss Associated With Omentioning

confidence: 99%

A Two-Component regulatory system with opposite effects on glycopeptide antibiotic biosynthesis and resistance

Alduina

Tocchetti²,

Costa

et al. 2020

Sci Rep

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The glycopeptide A40926, produced by the actinomycete Nonomuraea gerenzanensis, is the precursor of dalbavancin, a second-generation glycopeptide antibiotic approved for clinical use in the USA and Europe in 2014 and 2015, respectively. The final product of the biosynthetic pathway is an O-acetylated form of A40926 (acA40926). Glycopeptide biosynthesis in N. gerenzanensis is dependent upon the dbv gene cluster that encodes, in addition to the two essential positive regulators Dbv3 and Dbv4, the putative members of a two-component signal transduction system, specifically the response regulator Dbv6 and the sensor kinase Dbv22. The aim of this work was to assign a role to these two genes. Our results demonstrate that deletion of dbv22 leads to an increased antibiotic production with a concomitant reduction in glycopeptide resistance. Deletion of dbv6 results in a similar phenotype, although the effects are not as strong as in the Δdbv22 mutant. Consistently, quantitative RT-PCR analysis showed that Dbv6 and Dbv22 negatively regulate the regulatory genes (dbv3 and dbv4), as well as some dbv biosynthetic genes (dbv23 and dbv24), whereas Dbv6 and Dbv22 positively regulate transcription of the single, cluster-associated resistance gene. Finally, we demonstrate that exogenously added acA40926 and its precursor A40926 can modulate transcription of dbv genes but with an opposite extent: A40926 strongly stimulates transcription of the Dbv6/Dbv22 target genes while acA40926 has a neutral or negative effect on transcription of those genes. We propose a model in which glycopeptide biosynthesis in N. gerenzanensis is modulated through a positive feedback by the biosynthetic precursor A40926 and a negative feedback by the final product acA40926. In addition to previously reported control systems, this sophisticated control loop might help the producing strain cope with the toxicity of its own product. This work, besides leading to improved glycopeptide producing strains, enlarges our knowledge on the regulation of glycopeptide biosynthesis in actinomycetes, setting N. gerenzanensis and its two-component system Dbv6-Dbv22 apart from other glycopeptide producers. The glycopeptide antibiotic A40926 (Fig. 1A) is the precursor for dalbavancin (Fig. 1B), a semisynthetic lipoglycopeptide clinically used for treatment of acute skin infections caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and Streptococcus pyogenes. A40926 is produced by the actinomycete N. gerenzanensis as a complex of related compounds, differing mostly by the type of N-acyl chain attached to the glucuronic acid moiety. The core structure of A40926 consists of a heptapeptide containing the proteinogenic amino acid tyrosine and the non-proteinogenic amino acids 3,5-dihydroxyphenylglycine (DPG) and 4-hydroxyphenylglycine (HPG). The heptapeptide is assembled by a nonribosomal peptide synthetase (NRPS) and modified by the action of various enzymes: four oxygenases, one halogenase, one hydroxylase, two glycosyltransferases, one hexose ox...

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“…6b). Besides, analogous ABCF-mediated antibioticsignaling cascades can contribute to the cooperative competition, allowing strains with BGCs for functionally similar 50S ribosomal subunit-targeting antibiotics to synchronize the production and thus to improve the competitiveness over others (49). In the case of the LmrC-LmbU cascade, the cooperating strains would represent producers of antibiotics inducing lmrC expression, i.e., LSAP antibiotics and other molecules binding to the same site on the ribosome.…”

Section: Discussionmentioning

confidence: 99%

Beyond self-resistance: ABCF ATPase LmrC is a signal-transducing component of an antibiotic-driven signaling cascade hastening the onset of lincomycin biosynthesis

Koběrská

Veselá

Vimberg

et al. 2020

Preprint

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In natural environments, antibiotics are an important instrument of inter-species 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 the antibiotic production within the population. The entire cascade is encoded within the lincomycin biosynthetic gene cluster (BGC) and besides the transcriptional regulator, LmbU it consists of three lincomycin resistance proteins: a lincomycin transporter, LmrA, a 23S rRNA methyltransferase, LmrB, both conferring a high resistance, and an ABCF ATPase LmrC that confers only moderate resistance but is indispensable for the antibiotic-induced signal transduction. Specifically, the antibiotic sensing occurs via a ribosome-mediated attenuation, which activates LmrC production in response to lincosamide, streptogramin A, or pleuromutilin antibiotics. Then, the ribosome-operating LmrC ATPase activity 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 the ribosome-bound antibiotic and thus fine-tune the cascade. We propose that analogous ABCF-mediated signaling systems are relatively common because many BGCs for ribosome-targeting antibiotics encode an ABCF-protein accompanied by additional resistance protein(s) and transcriptional regulators. Moreover, we revealed that three of eight co-produced ABCF proteins of S. lincolnensis are clindamycin-responsive thus the ABCF-mediated antibiotic signaling might be generally utilized tool of chemical communication.IMPORTANCEResistance proteins are perceived as mechanisms protecting bacteria from the inhibitory effect of their produced antibiotic or antibiotics from competitors. Here, we report that antibiotic resistance proteins regulate lincomycin biosynthesis in response to subinhibitory concentrations of antibiotics. Particularly, we show the dual character of ABCF ATPase LmrC which confers antibiotic resistance and simultaneously transduces a signal from ribosome-bound antibiotic to gene expression, where the 5’ untranslated sequence upstream of its encoding gene functions as a primary antibiotic sensor. The ABCF-mediated antibiotic signaling can in principle function not only in the induction of antibiotic biosynthesis but in general 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 yet functionally inconsistent ABCF family involving the antibiotic resistance proteins and the translational regulators.

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Control of Specialized Metabolism by Signaling and Transcriptional Regulation: Opportunities for New Platforms for Drug Discovery?

Cited by 27 publications

References 123 publications

Transcription-factor centric genome mining strategy for discovery of diverse unprecedented RiPP gene clusters

Transcription-factor centric genome mining strategy for discovery of diverse unprecedented RiPP gene clusters

A Two-Component regulatory system with opposite effects on glycopeptide antibiotic biosynthesis and resistance

Beyond self-resistance: ABCF ATPase LmrC is a signal-transducing component of an antibiotic-driven signaling cascade hastening the onset of lincomycin biosynthesis

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