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Bacteria from the genus Streptomyces possess one of the most complex gene regulation machineries in the bacterial kingdom, allowing them to coordinate production of multiple compounds at discrete timing. Navigating through these regulatory networks to unlock the biosynthetic potential is challenging. Expression of silent biosynthetic gene clusters (BGCs) often occurs only under strict culture conditions and, as in the case of coelimycin, can be coordinated via quorum sensing. Here, we have investigated the interplay between coelimycin and actinorhodin production in the model organism Streptomyces coelicolor A3(2). We show that even the products of BGCs can have a regulatory function. The richness of potentially competing biosynthetic pathways may hinder high-yield biosynthesis of the desired product under fermentation conditions. Our results show the importance of designing host organisms with lowered background regulation by γ-butyrolactones for the desired biosynthetic pathway activation.

Members of the genus Paenibacillus play an important role in soil ecology, producing a range of important nonribosomal peptides (NRPs). A collection of plant-associated Paenibacillus spp. were analyzed for their phylogenetic and metabolic diversity. We developed a novel discovery pipeline that combines feature-based molecular networking with mass spectrometry query language queries to systematically prioritize bioactive NRPs containing basic amino acids. Thus, we provide a comprehensive genus-wide inventory of NRPs produced by Paenibacillus spp. We thereby identified the paenitracins, a new sub-family of bacitracins active against multidrug-resistant gram-positive pathogens. Our pipeline enables the discovery of novel peptidic natural products to accelerate the prioritization of chemical space for antibiotics.

Burkholderia is an incredibly diverse and versatile Gram-negative genus, within which over 80 species have been formally named and multiple other genotypic groups likely represent new species. Phylogenetic analysis based on the 16S rRNA gene sequence and core genome ribosomal multilocus sequence typing analysis indicates the presence of at least three major clades within the genus. Biotechnologically, Burkholderia are well-known for their bioremediation and biopesticidal properties. Within this review, we explore the ability of Burkholderia to synthesise a wide range of antimicrobial compounds ranging from historically characterised antifungals to recently described antibacterial antibiotics with activity against multiresistant clinical pathogens. The production of multiple Burkholderia antibiotics is controlled by quorum sensing and examples of quorum sensing pathways found across the genus are discussed. The capacity for antibiotic biosynthesis and secondary metabolism encoded within Burkholderia genomes is also evaluated. Overall, Burkholderia demonstrate significant biotechnological potential as a source of novel antibiotics and bioactive secondary metabolites.

Streptomyces bacteria are the major source of antibiotics and other secondary metabolites. Various environmental and physiological conditions affect the onset and level of production of each antibiotic by influencing concentrations of the ligands for conserved global regulatory proteins. In addition, as reviewed here, well-known autoregulators such as γ-butyrolactones, themselves products of secondary metabolism, accumulate late in growth to concentrations allowing their effective interaction with cognate binding proteins, in a necessary prelude to antibiotic biosynthesis. Most autoregulator binding proteins target the conserved global regulatory gene adpA, and/or regulatory genes for ‘cluster-situated regulators’ (CSRs) linked to antibiotic biosynthetic gene clusters. It now appears that some CSRs bind intermediates and end products of antibiotic biosynthesis, with regulatory effects interwoven with those of autoregulators. These ligands can exert cross-pathway effects within producers of more than one antibiotic, and when excreted into the extracellular environment may have population-wide effects on production, and mediate interactions with neighbouring microorganisms in natural communities, influencing speciation. Greater understanding of these autoregulatory and cross-regulatory activities may aid the discovery of new signalling molecules and their use in activating cryptic antibiotic biosynthetic pathways. This review highlights the roles of specialised metabolites, such as hormone-like autoregulators, antibiotic precursors and antibiotics themselves, in regulating antibiotic biosynthesis and mediating interspecies communication, and considers the ecological and evolutionary implications of this growing knowledge. Graphical Abstract Figure. This review highlights the roles of specialised metabolites, such as hormone-like autoregulators, antibiotic precursors and antibiotics themselves, in regulating antibiotic biosynthesis and mediating interspecies communication, and considers the ecological and evolutionary implications of this growing knowledge.

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 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.

Pantoea agglomerans DAPP-PG 734 was isolated as endophyte from knots (tumors) caused by Pseudomonas savastanoi pv. savastanoi DAPP-PG 722 in olive trees. To understand the plant pathogen-endophyte interaction on a genomic level, the whole genome of P. agglomerans DAPP-PG 734 was sequenced and annotated. The complete genome had a total size of 5′396′424 bp, containing one circular chromosome and four large circular plasmids. The aim of this study was to identify genomic features that could play a potential role in the interaction between P. agglomerans DAPP-PG 734 and P. savastanoi pv. savastanoi DAPP-PG 722. For this purpose, a comparative genomic analysis between the genome of P. agglomerans DAPP-PG 734 and those of related Pantoea spp. was carried out. In P. agglomerans DAPP-PG 734, gene clusters for the synthesis of the Hrp-1 type III secretion system (T3SS), type VI secretion systems (T6SS) and autoinducer, which could play an important role in a plant-pathogenic community enhancing knot formation in olive trees, were identified. Additional gene clusters for the biosynthesis of two different antibiotics, namely dapdiamide E and antibiotic B025670, which were found in regions between integrative conjugative elements (ICE), were observed. The in-depth analysis of the whole genome suggested a characterization of the P. agglomerans DAPP-PG 734 isolate as endophytic bacterium with biocontrol activity rather than as a plant pathogen.

Actinobacterial natural products showed a critical basis for the discovery of new antibiotics as well as other lead secondary metabolites. Varied environmental and physiological signals touch the antibiotic machinery that faced a serious decline in the last decades. The reason was exposed by genomic sequencing data, which revealed that Actinomycetes harbor a large portion of silent biosynthetic gene clusters in their genomes that encrypt for secondary metabolites. These gene clusters are linked with a great reservoir of yet unknown molecules, and arranging them is considered a major challenge for biotechnology approaches. In the present paper, we discuss the recent strategies that have been taken to augment the yield of secondary metabolites via awakening these cryptic genes in Actinomycetes with emphasis on chemical signaling molecules used to induce the antibiotics biosynthesis. The rationale, types, applications and mechanisms are discussed in detail, to reveal the productive path for the unearthing of new metabolites, covering the literature until the end of 2020.

During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in clinical practice. In addition to exploring new antibiotics, this makes it one of the research priorities of Actinomycetes to effectively increase the yield of antibiotics in production strains by various means. Most antibiotic-producing strains have a variety of functional regulatory factors that regulate their growth, development, and secondary metabolite biosynthesis processes. Through the study of precursor substances in antibiotic biosynthesis, researchers have revealed the precursor biosynthesis process and the mechanism by which precursor synthesis regulators affect the biosynthesis of secondary metabolites, which can be used to obtain engineered strains with high antibiotic production. This paper summarizes the supply of antibiotic biosynthesis precursors and the progress of research on the role of regulators in the process of precursors in biosynthesis. This lays the foundation for the establishment of effective breeding methods to improve antibiotic yields through the manipulation of precursor synthesis genes and related regulators.

Streptomyces bacteria are the primary source of clinically useful antibiotics. While many two-component systems have been linked to antibiotic biosynthesis in Streptomyces species, few have been well characterized. Here, we characterize a secretion stress-sensing two-component system called CutRS and propose a model for how the sensor kinase detects extracellular protein misfolding via two highly conserved cysteine residues. Importantly, we also show that deletion of cutRS triggers antibiotic overproduction in the presence of glucose. Since glucose normally represses antibiotic biosynthesis in Streptomyces species through carbon catabolite repression, this finding reveals a simple genetic route to bypass this barrier. This has significant implications for antibiotic discovery pipelines and industrial production, where glucose-rich media are preferred for cost and scalability. Our results position CutRS as a key target for future strain-improvement strategies.

Introducing novel antibiotics is essential to counter the spread of drug-resistant pathogens. Here, we report the discovery of 4′-thiothymidine (4′sT), a nucleoside antibiotic from the nematode symbiont Photorhabdus asymbiotica , identified through activation of a silent biosynthetic gene cluster. 4′sT features an unusual 4′-thiosugar moiety. We identified its biosynthetic gene cluster, including a radical SAM enzyme presumably involved in sulfur incorporation. 4′sT exhibits strain-selective activity that is governed by differences in thymidine metabolism rather than variations in the molecular target. These findings expand our knowledge of antibiotics with unusual selective activity.