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PubMed2024

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and fermentation but decreased ATP levels and growth, suggesting that Δagr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived "memory" of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Staphylococcus aureus↗

PubMed2024

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Staphylococcus aureus↗

PubMed2025

RRNPP quorum-sensing repertoires in the salivarius group genomes: overrepresentation and synchronous activation of SHP/Rgg systems in Streptococcus thermophilus.

UNLABELLED: In Bacillota, quorum sensing can be mediated by RRNPP regulators that are activated by autoinducing peptides (AIPs). In this study, we derived a hidden Markov model profile from a 3D-informed alignment to establish RRNPP repertoires for 527 genomes of streptococci in the salivarius group and identified probable AIPs. The salivarius group encompasses Streptococcus salivarius and Streptococcus vestibularis, which are part of the normal human oral microflora, and Streptococcus thermophilus, one of the most widely used bacteria in the dairy industry. We observed a large amount of plasticity in these repertoires, as well as profound differences among species. Notably, S. salivarius displayed an accumulation of ComR regulators, while S. thermophilus displayed an accumulation of Rgg regulators. The latter family included SHP-associated Rgg regulators, systems in which SHPs serve as AIPs; most of these regulators control the production of post-translationally modified peptides (RaS-RiPPs). Their level of richness contrasts with the genome reduction that accompanied S. thermophilus' adaptation to milk. We then used liquid chromatography-high resolution tandem mass spectrometry to analyze the activity of the eight most common SHP/Rgg systems by characterizing the SHPs and RaS-RiPPs found in the supernatants. We detected four SHPs and one RaS-RiPP that have never been seen before in S. thermophilus, and we showed that seven of the eight SHP/Rgg systems were functional. Finally, by simultaneously monitoring the amounts of both the SHPs and RaS-RiPPs, we demonstrated that the fates of these two peptide types differed during growth. SHP presence in the supernatant was transient, a pattern likely related to the peptides' signaling role. IMPORTANCE: Streptococcus thermophilus possesses an unusually high number of Rgg regulators, which are activated by SHP pheromones that control the production of RaS-RiPPs, peptides with cyclization motifs and growth inhibition properties. We conducted an in silico analysis of regulator repertoires across a wide range of strains; a subsequent experimental study revealed that the majority of the SHP/Rgg systems were functional. Employing an optimized liquid chromatography-high resolution tandem mass spectrometry protocol, we were able to better detect and follow SHP and RaS-RiPP accumulation. While RaS-RiPPs accumulated during growth, SHPs were only transiently present in the extracellular environment. This observation suggests that we could manipulate quorum sensing by adding SHPs to the growth medium and highlights the need to study the functions of the RaS-RiPPs.

Streptococcus thermophilus↗

PubMed2025

PqsE adapts the activity of the Pseudomonas aeruginosa quorum-sensing transcription factor RhlR to both autoinducer concentration and promoter sequence identity.

Pseudomonas aeruginosa is an opportunistic human pathogen that poses a significant health threat. Many pathogenic behaviors of P. aeruginosa are under control of the bacterial cell-cell communication system known as quorum sensing (QS). One of the QS master regulators, RhlR, is a receptor/transcription factor that not only relies on binding of its canonical ligand, N-butyrylhomoserine lactone (C4-HSL), but additionally requires a protein-protein interaction with the enzyme, PqsE. We constructed heterologous reporter strains in Escherichia coli that allow measurements of the reliance of RhlR on C4-HSL and/or PqsE binding for the ability to activate transcription of three RhlR-regulated genes: rhlA (PqsE independent), phzM (PqsE dependent), and azeB (PqsE inhibited). Analogous assays measuring activation of the three genes in P. aeruginosa were performed, and the patterns observed correlated tightly with the heterologous reporter assays. These results confirm that the binding of PqsE to RhlR is able to fine-tune RhlR transcription factor activity in a promoter-specific manner and prove that this ability is independent of other factors present in P. aeruginosa.IMPORTANCEPseudomonas aeruginosa is an opportunistic human pathogen that can cause fatal infections. There exists an urgent need for new, effective antimicrobial agents to combat P. aeruginosa. The PqsE-RhlR protein-protein interaction is essential for P. aeruginosa to be able to make toxins, form biofilms, and infect host organisms. In this study, we use both non-native models in Escherichia coli and measurements of gene expression/toxin production in P. aeruginosa to show that the PqsE-RhlR interaction enables fine-tuned gene expression and a heightened ability of P. aeruginosa to adapt to external conditions. These findings will be highly valuable as continued efforts are made to design inhibitors of the PqsE-RhlR interaction and test them as potential antimicrobial agents against P. aeruginosa infections.

Pseudomonas aeruginosa↗

PubMed2026

Investigating AHL-associated quorum sensing impact on antibiotic-driven resistome expansion in anaerobic fermentation microbiomes: Metagenomic insights.

Previous studies have demonstrated that quorum sensing (QS) can mitigate the impact of antibiotics on environmental microbial communities. Metagenomic analysis was used to examine AHL effects on the resistome in anaerobic fermentation microbiomes under antibiotic stress in this research. AHLs reduced ARGs, MGEs, and phage abundance compared to antibiotic-only samples following the addition of high concentrations (500 nmol/L) of AHLs. Phages and integrons played pivotal roles in shaping the resistome. Escherichia coli, Vibrio cholerae, and Pseudomonas aeruginosa were key targets affected by AHLs. Both the assembled environmental metagenomes and the complete genomes of isolated bacteria consistently support the broad potential of quorum-sensing systems in mediating the dissemination or regulation of resistome spreading. Quorum sensing systems are very likely to affect microbial community resistomes by regulating the phageome. These insights are valuable for refining fermentation and waste management processes, offering potential in environmental restoration and possibly curbing the spread of resistance genes.

Quorum Sensing↗

PubMed2026

Metagenome-resolved evidence that soluble factors in granular activated carbon-amended reactor effluent reprogram propionate metabolism and methanogenic pathways.

Granular activated carbon (GAC) enhances anaerobic digestion performance, yet the mechanisms underlying reactor-scale improvements remain incompletely understood, particularly how GAC affects biomass not attached to its surface. Here, sludge from a non-GAC up-flow anaerobic sludge blanket reactor was incubated with 0.45-μm-filtered effluents from non-GAC and GAC-amended reactors under repeated propionate loading, followed by genome-resolved metagenomics. GAC-reactor effluent increased methane yield from 64 ± 3% to 76 ± 3% (p < 0.01) in the absence of GAC particles. A non-redundant catalog of 170 quality-filtered metagenome-assembled genomes (MAGs) was recovered, enabling pathway- and gene-set quantification. Genomic potential for both major propionate-oxidation routes increased in the GAC-effluent group relative to the non-GAC group, with a larger increase for the methylmalonyl-CoA (MMC) route than for the dismutation route (1.289- versus 1.221-fold). Accordingly, the MMC-to-dismutation preference ratio was 5.60% higher in the GAC-effluent group, alongside a broader carrier base. Cobamide potential shifted toward remodeling and cobamide-dependent use rather than increased de novo corrin-ring synthesis. Candidate electron-transfer architectures were also rebalanced: PilA-associated carriers became less prominent, whereas maturation-supported multiheme cytochrome carriers increased from 22.96% to 34.90% of community abundance, although H2/formate-module carriers remained prevalent. Quorum-sensing systems underwent pathway- and carrier-specific redistribution, while all eight curated extracellular-polysaccharide modules showed higher mean gene abundance in the GAC-effluent composite. These findings show that a filter-passing effluent fraction can extend GAC-associated effects beyond direct particle contact and link enhanced methanogenesis to a broader, redistributed network of metabolic, redox, and coordination capacities. This expands the mechanistic framework of conductive-material-assisted anaerobic digestion and provides a basis for harnessing GAC-derived functions throughout the reactor.

Extracellular polymeric substances (EPS)↗

PubMed2026

Pseudomonas aeruginosa adaptation and persistence in the aspergilloma microbiome revealed by integrated multi-omics.

Chronic pulmonary aspergillosis involves the formation of a fungal ball (aspergilloma) in lung cavities. Pseudomonas aeruginosa commonly co-colonizes these lesions; however, the in vivo mechanisms underlying its persistence are unknown. Using a multi-omics approach on resected aspergillomas, we defined the genomic, transcriptional, and metabolic adaptations of P. aeruginosa within this polymicrobial niche. We reconstructed high-quality P. aeruginosa genomes and identified a conserved core genome, along with accessory genes for secondary metabolism, virulence, and antimicrobial resistance. Phylogenomics revealed heterogeneous evolutionary paths among co-colonizing strains. Metatranscriptomics showed stark physiological heterogeneity, from metabolically aggressive to stress-adapted states. High expression of phenazine, quorum-sensing (PQS), siderophore, and secretion-system operons was corroborated by metabolomic detection of phenazine-1-carboxylic acid and 2-heptylquinolin-4(1H)-one, confirming active bacterial antagonism in vivo. Concurrent Aspergillus fumigatus transcriptomics revealed the activation of oxidative stress responses, secondary metabolism (eg fumagillin), and iron scavenging, demonstrating reciprocal competition. Host transcriptomics revealed patient-specific immune signatures that correlated with the metabolic activity of the co-colonizers. This work provides an integrated systems-level analysis of the tri-kingdom aspergilloma ecosystem. P. aeruginosa persistence is driven by genomic plasticity and context-dependent expression of competitive pathways, shaped within a chronic inflammatory environment. These findings redefine aspergillomas as active polymicrobial consortia, establishing a framework for targeting resilient microbial communities in chronic lung disease.

Multiomics↗

PubMed2025

Quorum sensing and DNA methylation play active roles in clinical Burkholderia phase variation.

Phenotypic diversity in bacteria often results from adaptation to changing environmental conditions, exemplified by variable colony morphotypes. In Burkholderia pseudomallei, discrete genomic alterations and modulation of gene expression facilitate adaptation. Adapted variants of species within the Burkholderia cepacia complex (Bcc) often lose the pC3 virulence megaplasmid, impacting their colony morphology and their production of virulence factors. In this study, we characterize variants arising in Burkholderia ambifaria clinical isolates using proteomics and phenotypic tests and show that some of them have retained the pC3, indicating a distinct phase variation mechanism at play in this Bcc species. Interestingly, variants of B. ambifaria strains CEP0996 (pC3-null) and HSJ1 (pC3-positive) still share similarities in phenotypes controlled by the Cep quorum-sensing (QS) system. We further investigated the role of QS in B. ambifaria HSJ1 phase variation and confirmed that the Cep QS system is important for the emergence of variants. Given that DNA methylation is a key epigenetic factor regulating virulence factors in Burkholderia cenocepacia, we hypothesized that adenosine DNA methylation also governs phase variation in B. ambifaria HSJ1. By deleting the genes encoding putative adenosine DNA methyltransferases, we discovered that an orphan type II DNA methyltransferase inhibits the emergence of phase variants. This study is the first to demonstrate that quorum sensing and adenosine DNA methylation are two antagonistic systems independently controlling phase variation in B. ambifaria.IMPORTANCESome Burkholderia species are pathogenic to plants, animals, or humans. In immunocompromised individuals, and people suffering from cystic fibrosis, infection from the Burkholderia cepacia complex (Bcc) can lead to "cepacia syndrome." In northern Australia and southeast Asia, melioidosis caused by Burkholderia pseudomallei is prevalent among native population, particularly among people with diabetes, chronic lung or kidney disease or alcoholism. Burkholderia's phenotypic plasticity, including colony morphotype variation (CMV), enables rapid adaptation to diverse environments, enhancing its survival and pathogenicity. This study reveals phase variation as a new CMV mechanism within the Bcc group and is the first to report that quorum sensing and DNA methylation are involved in phase variation. Understanding the underlying mechanisms of CMV could lead to the development of targeted therapies against these highly antibiotic-tolerant bacteria.

Quorum Sensing↗

PubMed2026

Intra-strain genomic microevolution and phage resistance in Pseudomonas aeruginosa PAO1 laboratory isolates.

Pseudomonas aeruginosa is a major opportunistic pathogen, and its laboratory reference strain, PAO1, is widely used in microbiological and genetic studies. However, PAO1 often exhibits phenotypic variability that can affect experimental reproducibility. Our PAO1 stock, obtained from a public biobank, is resistant to PP7, a pilus-dependent single-stranded RNA phage known to infect PAO1. This suggests the presence of genetic variants in the stock. To check this possibility, we isolated six phenotypically distinct variants (GU1-GU6) and performed genomic and phenotypic analyses. Notable differences were observed among the isolates in terms of motility, pyocyanin production, and susceptibility to PP7. Whole-genome sequencing revealed that four of the six variants harbored mutations in pilus-associated genes. Among these, GU3 carried a mutation in pilT, which encodes a motor protein essential for type IV pilus retraction, and the loss of retraction led to the PP7 resistance. GU2, GU4, and GU6 shared a nonsense mutation in pilJ, a gene involved in chemotaxis and pilus extension, resulting in reduced twitching motility and lower PP7 infection efficiency. Additionally, we found that a mutation in lasR, a master regulator of quorum sensing, promoted the replication of prophage Pf6, which was integrated into the PAO1 genome. Pf6 replication interferes with PP7 infection, providing an alternative mechanism of resistance. These findings offer new insights into the complexity of phage-host interactions and emphasize the importance of routine verification and careful handling of P. aeruginosa sublines used in bacteriological and phage research.IMPORTANCEPhenotypic and genotypic variability in Pseudomonas aeruginosa PAO1 has been widely reported, raising concerns regarding the reproducibility of laboratory studies that rely on this reference strain. In this study, we isolated six PAO1 variants from a single laboratory stock and demonstrated that they differed markedly in motility, pyocyanin production, and susceptibility to the ssRNA phage PP7. Whole-genome sequencing has revealed that even a single mutation in a pilus-associated gene can profoundly affect bacterial motility and phage susceptibility. Furthermore, we showed that a mutation in lasR, a key regulator of the quorum-sensing system, triggered replication of the Pf6 prophage, which in turn hindered PP7 infection. These findings underscore the dynamic nature of laboratory strains and highlight the need for caution when interpreting results from phage-host interaction studies using reference strains. Our results provide a new understanding of how subtle genetic changes in model strains influence experimental outcomes in microbiology.

Pseudomonas aeruginosa↗

PubMed2026

Whole-genome profiling of antimicrobial resistance and virulence determinants in extensively-drug resistant Pseudomonas aeruginosa isolates causing ventilator associated pneumonia in Egypt.

Among critically ill ICU patients under prolonged mechanical ventilation, Pseudomonas aeruginosa is one of the most common cause of ventilator-associated pneumonia (VAP), with antimicrobial pressure leading to emergence of multidrug, extensively drug and pandrug-resistant (PDR) strains. In Egypt, very little genomic data exist on P. aeruginosa associated with VAP. This study aimed at characterizing the antimicrobial resistance (AMR) determinants, virulence repertoire, MGEs, and sequence types of two highly drug-resistant Pseudomonas aeruginosa isolates, including one pandrug-resistant colistin-resistant isolate and one extensively drug-resistant colistin-susceptible isolate from respiratory tract of Egyptian ICU patients suffering from VAP. The two isolates were identified conventionally and confirmed to the species level using MALDI-TOF MS. Antibiotic susceptibility was assessed using the VITEK-2 Compact system and the broth microdilution method. Genome analysis was performed using PATRIC, ResFinder, CARD, and Mobile Element Finder. For both isolates, resistance was found to all antibiotics routinely tested, however, one isolate had high-level colistin resistance (MIC > 64 µg/mL), while the other isolate was still colistin susceptible. Whole-genome sequencing identified two rare sequence types, ST2023 and ST2685, both 6.5-7.6 Mb in size with a 66% GC content. The presence of 21 MGEs in the SRR36105565 genome shows that it has high genomic flexibility, including a broader resistome than other strains, such as blaVIM-2 and OXA variants, aminoglycoside-modifying enzymes, crpP, and disinfectant-resistance markers. Both isolates retained large virulence determinants including Type III and Type VI secretion systems, alginate regulation genes, quorum-sensing networks, and siderophore biosynthesis clusters. It also represents one of the first genomic studies of VAP associated PDR P. aeruginosa from Egypt. The combination of widespread AMR with intact virulence supports the potential value of future genomic surveillance efforts and improved antimicrobial stewardship in local ICUs.

Pneumonia, Ventilator-Associated↗

PubMed2026

Synthetic community derived from the root core microbes of a desert shrub Caragana korshinskii enhances wheat drought tolerance.

BACKGROUND: Drought, intensified by climate change, poses a mounting threat to global food security by severely constraining crop productivity. While microbial inoculants offer promise for drought tolerance, their poor adaptability remains insufficient for extremely water-deficient environments. Desert plants host unique drought-adapted microbiomes that remain largely unexplored for agricultural applications. RESULTS: Here, we investigated the microbial community of the desert shrub Caragana korshinskii and identified a core set of drought-responsive strains. A synthetic microbial community (SynCom) derived from these strains significantly improved wheat growth under drought stress. Metagenomic analyses revealed that microbial functions related to biofilm formation, quorum sensing, and carbon metabolism were enriched, with Pseudomonas identified as a key functional taxon. Guided by inter-strain interactions in biofilm assembly, we streamlined the consortium into a five-member synthetic community, where quorum-sensing signals promoted community-wide biofilm formation. Community biofilm production improved strain colonization and conferred greater drought tolerance compared to monocultures. In plants, mechanistic investigations indicated that the simplified SynCom inoculation universally upregulated MAPK and jasmonic acid signaling pathways. Furthermore, carbohydrate metabolic pathways such as starch and sucrose metabolism were specifically activated, suggesting a multi-level mechanism underlying SynCom-mediated drought tolerance. CONCLUSIONS: These findings demonstrate that SynCom constructed on the endophytic flora of desert plants can significantly enhance crop drought tolerance. Our work highlights the pivotal role of community biofilm synthesis in facilitating root colonization and activating a multidimensional drought tolerance network in plants. This study not only gives an ecological perspective on desert microbiome adaptations but also offers a strategic framework for developing effective microbial inoculants for arid-region agriculture. Video Abstract.

Caragana↗