mSystems最新文献

The global crisis of antimicrobial resistance poses a major threat to human health, underscoring the urgency of developing new antibacterial strategies. Antimicrobial peptides (AMPs) are promising alternatives to antibiotic therapy, yet potential microbial resistance is of great concern. Resistance is often accompanied by fitness costs, which may in turn influence the spread of drug-resistant bacteria and their susceptibility to other antimicrobial agents. Herein, we investigate the evolutionary trajectory of bacterial resistance to antibiotics and AMPs in Escherichia coli, and evaluate the fitness costs and collateral sensitivity of drug-resistant strains. We reveal that E. coli develops resistance to antibiotics, particularly ciprofloxacin and kanamycin, at a notably faster rate than to AMPs. Moreover, antibiotic-evolved strains exhibit slightly higher fitness costs than AMP-evolved bacteria, primarily manifested in reduced bacterial growth and swimming motility. Notably, we demonstrate that trimethoprim-resistant E. coli, with mutations in thyA gene, displays enhanced susceptibility to pexiganan, as evidenced by both in vitro and in vivo studies. Overall, our findings shed new insights for the clinical deployment of AMPs and propose innovative therapeutic strategies for combating antibiotic-resistant bacterial infections.IMPORTANCEThe global spread of antimicrobial resistance necessitates the development of innovative anti-infective strategies. Antimicrobial peptides (AMPs) represent promising alternatives in the post-antibiotic era. By monitoring the evolutionary trajectory of bacterial resistance to eight antibiotics and ten AMPs in Escherichia coli, we demonstrate that E. coli exhibits slower emergence of resistance against AMPs compared with antibiotics. Additionally, these antibiotic-resistant strains incur significant fitness costs, particularly in bacterial growth and motility. Most importantly, we find that some antibiotic-resistant strains show collateral sensitivity to specific AMPs in both in vitro and animal infection models, which is conducive to accelerating the development of AMP-based antibacterial treatment.

Colon cancer (CC) is one of the most common cancers globally, which is associated with the gut microbiota intimately. In current research, exploring the complex interaction between microbiomes and CC is a hotspot. However, the information on microbiomes in most previous studies is based on fecal, which does not fully display the microbial environment of CC. Herein, we collected mucosal and tissue samples from both the tumor and normal regions of 19 CC patients and clarified the composition of mucosal microbiota by 16S rRNA and metagenomic sequencing. Additionally, RNA-Seq was also conducted to identify the different expression genes between tumor and normal tissue samples. We revealed significantly different microbial community structures and expression profiles to CC. Depending on correlation analysis, we demonstrated that 1,472 genes were significantly correlated with CC tumor microbiota. Our study reveals a significant enrichment of Campylobacter jejuni in the mucosa of CC, which correlates with bile secretion. Additionally, we observe a negative correlation between C. jejuni and immune cells CD4+ Tem and mast cells. Finally, we discovered that metabolic bacterial endosymbiont of Bathymodiolus sp., Bacillus wiedmannii, and Mycobacterium tuberculosis had a significant survival value for CC, which was ignored by previous research. Overall, our study expands the understanding of the complex interplay between microbiota and CC and provides new targets for the treatment of CC.

Importance: This study contributes to our understanding of the interaction between microbiota and colon cancer (CC). By examining mucosal and tissue samples rather than solely relying on fecal samples, we have uncovered previously unknown aspects of CC-associated microbiota. Our findings reveal distinct microbial community structures and gene expression profiles correlated with CC progression. Notably, the enrichment of Campylobacter jejuni in CC mucosa, linked to bile secretion, underscores potential mechanisms in CC pathogenesis. Additionally, observed correlations between microbial taxa and immune cell populations offer new avenues for immunotherapy research in CC. Importantly, this study introduces CC-associated microbiota with survival implications for CC, expanding therapeutic targets beyond conventional strategies. By elucidating these correlations, our study not only contributes to uncovering the potential role of gut microbiota in colon cancer but also establishes a foundation for mechanistic studies of gut microbiota in colon cancer, emphasizing the broader impact of microbiota research on cancer biology.

Toxin-antitoxin (TA) systems consist of toxic proteins and their inhibitors, and were originally shown to ensure plasmid maintenance in bacterial populations. Over time, however, TA systems have also been identified on bacterial chromosomes, raising questions about their roles unrelated to plasmid stability. Among the eight currently recognized types of TA systems, type II has been the most extensively investigated. Type II systems are often found in pathogenic bacterial species, including staphylococci. Staphylococcus aureus, a notorious human pathogen, harbors multiple type II TA systems, both plasmid- and chromosome-encoded, while their potential relation to virulence remains to be addressed. Here, we investigate the co-occurrence of TA systems and antibiotic resistance (AR) determinants in S. aureus, focusing on the potential negative impact of type II toxin RNases on antibiotic resistance. We considered both well-characterized and newly characterized TA loci of S. aureus. Our findings demonstrate a relationship between TA systems and AR determinants, wherein TA systems negatively affect antibiotic resistance. Due to substantial selective pressure, the migration of TA systems from plasmids to chromosomes results in their inactivation. This observation may be an important factor shaping the spread and evolution of both TA systems and AR determinants in bacteria. We exemplify this phenomenon in detail using the well-known PemIK-Sa1 system and a newly identified SCCmec-related PemIK-Sa6 system characterized in this study.

Importance: Toxin-antitoxin (TA) systems are entities unique to bacteria. They are involved in the maintenance of mobile genetic elements (MGEs), regulation of gene expression and bacterial virulence. Staphylococcus aureus is a dangerous human pathogen with increasing antibiotic resistance (AR). The maintenance and dissemination of AR determinants is often driven by MGEs, which link AR and TA systems. Our study identified a negative correlation between TA systems and AR determinants in S. aureus. Furthermore, we have shown that the expression of a toxic component of an exemplary TA system negatively affects antibiotic resistance. We argue that in particular strains, a selective pressure maintains either the TA system or AR determinant. Alternatively, TA systems are inactivated by mutations when present together with AR determinants to maintain the functionality of the latter. Our observations uncover an important factor shaping the spread and evolution of both TA systems and AR determinants in bacteria, which is especially relevant to pathogenic species.

Flavonoids, a major component of plant root exudates, play a crucial role in mediating plant-microbe interactions. However, the mechanisms by which flavonoids are perceived and trigger downstream signaling events in microbes remain largely unknown. In this study, we characterized AefR, a flavonoid-sensing transcriptional regulator from Pseudomonas fluorescens 2P24, a plant growth-promoting rhizobacterium (PGPR) known for its biocontrol properties. AefR was found to repress the expression of the mexEF-oprN efflux pump, which putatively exports N-acylhomoserine lactones (AHLs). This repression attenuates the PcoR/PcoI quorum-sensing system, leading to decreased production of the antibiotic mupirocin in P. fluorescens 2P24. Furthermore, quantitative proteomic analysis revealed that the PcoR/PcoI quorum-sensing system regulates a diverse range of physiological processes, including mupirocin production and denitrification. Collectively, these findings demonstrate a quorum-quenching role of flavonoids in a PGPR strain, establishing that flavonoids can disrupt quorum-sensing by enhancing the efflux of quorum-sensing signaling molecules. These findings have practical implications for the development of sustainable biocontrol strategies, where leveraging natural plant-microbe interactions could enhance the suppression of plant pathogens without the use of synthetic chemicals.IMPORTANCEFlavonoids are key mediators of plant-microbe interactions; however, their role in regulating microbial signaling remains poorly understood. This study identifies AefR as a flavonoid-sensing regulator in Pseudomonas fluorescens 2P24, revealing a novel quorum-quenching mechanism where flavonoids enhance the efflux of quorum-sensing signals. These findings shed light on the molecular basis of flavonoid-mediated microbial regulation and offer new strategies for sustainable plant health management.

Acute gastrointestinal injury (AGI) is known for its poor long-term prognosis and the associated increase in mortality among intensive care unit (ICU) patients. As the role of the gut microbiome and resistome in AGI remains unclear, the present study aimed to explore the possible associations between dysbacteriosis and in-hospital mortality in ICU patients with gastrointestinal dysfunction. Fecal samples were collected from a prospective cohort of 210 ICU patients with AGI, and shotgun metagenomic sequencing was used to determine the taxonomic composition of gut microbiota and the differences of antibiotic resistance genes (ARGs) between the Death and Survival groups. Compared to the Survival group, patients in the Death group shifted from strict anaerobes to facultative anaerobes in the fecal microbial community, with more Klebsiella but less Prevotella. The co-occurrence patterns revealed that more ARG subtypes were enriched in microbial taxa in the Death group, especially for Clostridium and Methanobrevibacter. Furthermore, the ARG type had large area under the curve (AUCs) in receiver operating characteristic for predicting the disease severity, and a combined gut microbiota-ARG subtype classifiers showed better performance than either of them. Thus, comparative metagenome-associated analysis can help to obtain valuable information about gut microbiota and gene coding for antibiotic resistance in AGI patients.

Importance: A metagenomic-related strategy was conducted to obtain a highly valuable resource to improve understanding of intestinal microbiota dysbiosis and antibiotic resistance genes (ARGs) profiles. The results indicate that intestinal microbiota, including Klebsiella and Prevotella, changed dramatically in intensive care unit (ICU) patients with acute gastrointestinal injury (AGI). Due to longer ICU stays and receiving more antibiotic treatment, the types and correlations of ARGs in the Death group were significantly higher than those in the Survival group. The findings of this study are expected to expand our knowledge of gut microbiota and resistome profiles reflecting gastrointestinal status, accelerate the identification of disease biomarkers, and provide new insights into the prevention and treatment of AGI-related diseases.

The incidence of colorectal cancer (CRC) has been increasing in recent decades. Current methods for CRC screening have their own drawbacks, thus there is an urgent need to identify the key microbes that drive the development of CRC for wider application in the early detection and prevention of CRC. To address this issue, we performed fecal microbiome analysis by high-throughput sequencing of 16S rRNA gene combined with blood biochemical indicators in patients with CRC stages I, II, III, and IV, healthy people, and patients with polyps. Fecal microbiota of patients with CRC was disturbed, as evidenced by significantly reduced α-diversity in patients with CRC stage IV and markedly different β-diversity. The random forest model identified the top 25 genera from 174 training data, resulting in a diagnostic accuracy of 87.95%. Further, by combining with differential genera analysis, we screened out 11 biomarkers that significantly changed in different groups. Peptostreptococcus, Parvimonas, Shewanella, Oscillibacter, Eggerthella, and Gemella associated with the development of CRC were significantly enriched, while Fenollaria, Staphylococcus, Ezakiella, Finegoldia, and Neisseria associated with the remission of CRC were significantly suppressed in patients with CRC. Importantly, carcinoembryonic antigen (CEA) was significantly correlated with these 11 microbial biomarkers, and carbohydrate antigen 19-9 (CA 19-9) was markedly correlated with Oscillibacter. Notably, co-occurrence network analysis at the genus level exhibited that the microbial co-occurrence network of CRC IV was the most complex and stable. These results suggested that CEA, CA 19-9 and 11 microbial biomarkers may be co-biomarkers for the disease occurrence and development, and non-invasive diagnosis of CRC.

Importance: Identifying the key microbes that drive the development of colorectal cancer (CRC) has been important in this field. We delved into the research on the association between CRC and fecal microbiota in this study, providing a detailed analysis of the characteristics of fecal microbiota during the transition from normal intestine to polyps to cancer. Fecal bacterial biomarkers and blood biochemical indicators may be co-biomarkers in the development of CRC.

This study aimed to elucidate the complement protein C3-mediated host-pathogen interaction in the brain abscess caused by Staphylococcus aureus infection. Dual RNA-seq was employed to analyze the transcriptomic differences between C3 deficiency and wild-type mice of S. aureus-induced brain abscess model, and then we investigated the potential regulatory pathways of S. aureus-host interaction mediated by C3 and S. aureus genes associated with the pathogenesis of brain abscess. Finally, C3 deficient-mice and hla mutants of S. aureus were used to verify the specific pathogen-host interaction. In the S. aureus-induced brain abscess mouse model, the transcriptomic analysis revealed significant changes in bacterial virulence factors, such as hemolysin. Based on these data, we predicted a regulatory network formed by genes like hrcA and dnaK, which represent a possible regulation mechanism of S. aureus responding to the host. Furthermore, we identified that hla was the C3 response gene in S. aureus. From the host perspective, we observed that the absence of C3 significantly impacted the host's inflammatory response, primarily by altering the gene expression of several key immune and inflammatory pathways. These findings suggest that C3 deficiency may impair the host's ability to recognize and respond to external pathogens. To the best of our knowledge, this study proposed that S. aureus may affect host immune response through C3, and C3 plays a critical role in regulating inflammation and immune signaling pathways in the brain abscess caused by S. aureus infection.IMPORTANCEIn this work, we employed immunofluorescence and Western blot analysis to reveal a significant upregulation of microglia-derived C3 in the brain abscess mice model caused by S. aureus infection. By integrating the individual RNA sequencing data of S. aureus and the dual RNA-seq data of S. aureus infection brain abscess mice model, the potential regulatory pathways between S. aureus and host were identified, and host C3 not only affects the immune response but also mediates the regulation network of S. aureus. This study provided the potential novel targets for therapeutic strategies in mitigating the effects of S. aureus infections and improving treatment outcomes.

Encoded within many microbial genomes, biosynthetic gene clusters (BGCs) underlie the synthesis of various secondary metabolites that often mediate ecologically important functions. Several studies and bioinformatics methods developed over the past decade have advanced our understanding of both microbial pangenomes and BGC evolution. In this minireview, we first highlight challenges in broad evolutionary analysis of BGCs, including delineation of BGC boundaries and clustering of BGCs across genomes. We further summarize key findings from microbial comparative genomics studies on BGC conservation across taxa and habitats and discuss the potential fitness effects of BGCs in different settings. Afterward, recent research showing the importance of genomic context on the production of secondary metabolites and the evolution of BGCs is highlighted. These studies draw parallels to recent, broader, investigations on gene-to-gene associations within microbial pangenomes. Finally, we describe mechanisms by which microbial pangenomes and BGCs evolve, ranging from the acquisition or origination of entire BGCs to micro-evolutionary trends of individual biosynthetic genes. An outlook on how expansions in the biosynthetic capabilities of some taxa might support theories that open pangenomes are the result of adaptive evolution is also discussed. We conclude with remarks about how future work leveraging longitudinal metagenomics across diverse ecosystems is likely to significantly improve our understanding on the evolution of microbial genomes and BGCs.

Natural products are a critical source of novel chemotypes for drug discovery. However, the implementation of natural product extract libraries in high throughput screening is hampered by natural product structural redundancy and potential for bioactive re-discovery. This challenge and large library sizes drastically increase the time and cost during initial high throughput screens. To address these limitations, we developed a method that leverages liquid chromatography-tandem mass spectrometry spectral similarity to dramatically reduce natural product library size, with minimal bioactive loss, and applied this to a collection of fungal extracts. Importantly, this method also afforded increased bioassay hit rates against microbial targets, with broad applicability across assays and natural product sources. Thus, this method offers a broadly applicable strategy for accelerated and cost-effective natural product drug discovery.

Importance: Natural product libraries are large collections of extracts derived from fungi, plants, bacteria, or any other natural sources. These libraries play an important role in the initial phases of drug discovery, providing the basis for bioassays against a target of interest. However, these collections often comprise thousands of extracts with sometimes overlapping chemical structures, which can result in a bottleneck in both time and costs for the initial phases of drug discovery. Here, we have developed a method that uses mass spectrometry to dramatically reduce the size of these libraries, with minimal tradeoffs and improved success rates in bioassays. Ultimately, this will speed up the process of bioactive candidate identification and isolation, and drug development overall.