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Microbiology Spectrum Jul 2024Growing numbers of infections caused by antibiotic-resistant strains are a major concern for healthcare systems that will require new antibiotics for treatment as well...
Growing numbers of infections caused by antibiotic-resistant strains are a major concern for healthcare systems that will require new antibiotics for treatment as well as preventative measures that reduce the number of infections. Lipopeptides are antimicrobial molecules, of which some are used as antibiotics, including the last resort antibiotics daptomycin and polymyxins. Here we have studied the antimicrobial effect of the cyclic lipopeptide viscosin on growth and morphology. Most lipopeptides function as surfactants that create pores in membrane layers, which is regarded as their main antimicrobial activity. We show that viscosin can inhibit growth of without disintegration of the cytoplasmic membrane. Instead, the cells developed abnormal shapes and misplaced new division sites. The cell wall of these bacteria appeared less dense in electron microscopy images, suggesting that viscosin interfered with normal cell wall synthesis. Corroborating this observation, a luciferase reporter assay was used to show that the two-component systems LiaFSR and CiaRH, which are known to be activated upon cell wall stress, were strongly induced by viscosin. Furthermore, a mutant displaying 1.8-fold decreased susceptibility to viscosin was generated by sequential exposure to increasing concentrations of the lipopeptide. The mutant suffered from significant fitness loss and had mutations in genes involved in fatty acid synthesis, teichoic acid synthesis, and cell wall synthesis as well as transcription and translation. How these mutations might be linked to decreased viscosin susceptibility is discussed.IMPORTANCE is a leading cause of bacterial pneumonia, sepsis, and meningitis in children, and the incidence of infections caused by antibiotic-resistant strains is increasing. Development of new antibiotics is therefore necessary to treat these types of infections in the future. Here, we have studied the activity of the antimicrobial lipopeptide viscosin on and show that in addition to having the typical membrane destabilizing activity of lipopeptides, viscosin inhibits pneumococcal growth by obstructing normal cell wall synthesis. This suggests a more specific mode of action than just the surfactant activity. Furthermore, we show that does not easily acquire resistance to viscosin, which makes it a promising molecule to explore further, for example, by synthesizing less toxic derivates that can be tested for therapeutic potential.
PubMed: 38958463
DOI: 10.1128/spectrum.00624-24 -
Unveiling the dance of evolution: Pla-mediated cleavage of Ymt modulates the virulence dynamics of .MBio Jul 2024has recently evolved into a highly lethal flea-borne pathogen through the pseudogenization of extensive genes and the acquisition of exogenous plasmids. Particularly...
UNLABELLED
has recently evolved into a highly lethal flea-borne pathogen through the pseudogenization of extensive genes and the acquisition of exogenous plasmids. Particularly noteworthy are the newly acquired pPCP1 and pMT1 plasmids, which encode the virulence determinants Pla and murine toxin (Ymt), crucial for subcutaneous infection and survival within flea vector of , respectively. This study reveals that Pla can cleave Ymt at K299 both and expressing Ymt displays enhanced biofilm formation and increased blood survival, indicating significant roles of Pla-mediated Ymt cleavage in these phenotypes. Intriguingly, although both the ancestral form of Pla and the prevalent Pla-I259T variant in modern strains are capable of cleaving Ymt at K299, the cleavage efficiency of Pla-I259T is only half that of the ancestral variant. In subcutaneous infection, mice infected with ΔK299A show significantly prolonged survival compared to those infected with Δ. Similarly, infection with ΔI259T also results in extended survival compared to Δ infection. These data demonstrate that the I259T substitution of Pla mitigates the enhanced virulence of in mice caused by Pla-mediated Ymt cleavage, thereby prolonging the survival period of infected animals and potentially conferring advantages on the transmission of to the next host. These findings deepen our understanding of the intricate interplay between two newly acquired plasmids and shed light on the positive selection of the Pla-I259T mutation, providing new insights into the virulence dynamics and transmission mechanisms of .
IMPORTANCE
The emergence of as a highly lethal pathogen is driven by extensive gene pseudogenization and acquisition of exogenous plasmids pPCP1 and pMT1. However, the interplay between these two plasmids during evolution remains largely unexplored. Our study reveals intricate interactions between Ymt and Pla, two crucial virulence determinants encoded on these plasmids. Pla-mediated cleavage of Ymt significantly decreases survival in mouse blood and enhances its virulence in mice. The prevalent Pla-I259T variant in modern strains displays reduced Ymt cleavage, thereby extending the survival of infected animals and potentially increasing strain transmissibility. Our findings shed light on the nuanced evolution of , wherein reduced cleavage efficiency is a positive selection force, shaping the pathogen's natural trajectory.
PubMed: 38958447
DOI: 10.1128/mbio.01075-24 -
Microbiology Resource Announcements Jul 2024The draft genome of a previously documented potential probiotic strain GM93m3 from raw goat milk in Nigeria is reported. The total genome size was 2,447,229 with 46...
The draft genome of a previously documented potential probiotic strain GM93m3 from raw goat milk in Nigeria is reported. The total genome size was 2,447,229 with 46 contigs and G+C content of 44.86%.
PubMed: 38958438
DOI: 10.1128/mra.00270-24 -
Database : the Journal of Biological... Jul 2024Myxobacteria are predatory bacteria with antimicrobial activity, utilizing complex mechanisms to kill their prey and assimilate their macromolecules. Having large...
Myxobacteria are predatory bacteria with antimicrobial activity, utilizing complex mechanisms to kill their prey and assimilate their macromolecules. Having large genomes encoding hundreds of secondary metabolites, hydrolytic enzymes and antimicrobial peptides, these organisms are widely studied for their antibiotic potential. MyxoPortal is a comprehensive genomic database hosting 262 genomes of myxobacterial strains. Datasets included provide genome annotations with gene locations, functions, amino acids and nucleotide sequences, allowing analysis of evolutionary and taxonomical relationships between strains and genes. Biosynthetic gene clusters are identified by AntiSMASH, and dbAMP-generated antimicrobial peptide sequences are included as a resource for novel antimicrobial discoveries, while curated datasets of CRISPR/Cas genes, regulatory protein sequences, and phage associated genes give useful insights into each strain's biological properties. MyxoPortal is an intuitive open-source database that brings together application-oriented genomic features that can be used in taxonomy, evolution, predation and antimicrobial research. MyxoPortal can be accessed at http://dicsoft1.physics.iisc.ac.in/MyxoPortal/. Database URL: http://dicsoft1.physics.iisc.ac.in/MyxoPortal/. Graphical Abstract.
Topics: Myxococcales; Genome, Bacterial; Databases, Genetic; Genomics
PubMed: 38958433
DOI: 10.1093/database/baae056 -
Brazilian Journal of Medical and... 2024Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of mortality by a single infectious agent in the world. M. tuberculosis infection...
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of mortality by a single infectious agent in the world. M. tuberculosis infection could also result in clinical chronic infection, known as latent TB infection (LTBI). Compared to the current limited treatment, several subunit vaccines showed immunotherapeutic effects and were included in clinical trials. In this study, a subunit vaccine of Ag85B with a novel mucosal adjuvant c-di-AMP (Ag85B:c-di-AMP) was delivered intranasally to a persistent M. tuberculosis H37Ra infection mouse model, which also presented the asymptomatic characteristics of LTBI. Compared with Ag85B immunization, Ag85B:c-di-AMP vaccination induced stronger humoral immune responses, significantly higher CD4+ T cells recruitment, enhanced Th1/Th2/Th17 profile response in the lung, decreased pathological lesions of the lung, and reduced M. tuberculosis load in mice. Taken together, Ag85B:c-di-AMP mucosal route immunization provided an immunotherapeutic effect on persistent M. tuberculosis H37Ra infection, and c-di-AMP, as a promising potential mucosal adjuvant, could be further used in therapeutic or prophylactic vaccine strategies for persistent M. tuberculosis infection as well as LTBI.
Topics: Animals; Adjuvants, Immunologic; Tuberculosis Vaccines; Mycobacterium tuberculosis; Mice; Disease Models, Animal; Female; Antigens, Bacterial; Acyltransferases; Vaccines, Subunit; Bacterial Proteins; Tuberculosis; Latent Tuberculosis; Mice, Inbred BALB C; Administration, Intranasal
PubMed: 38958367
DOI: 10.1590/1414-431X2024e13409 -
Brazilian Journal of Medical and... 2024Jiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral...
Jiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral ischemic symptoms in clinical practice, but the underlying mechanisms are unclear. In this study, we investigated the mechanisms of action of JXCG in the treatment of IS by combining metabolomics with network pharmacology. The chemical composition of JXCG was analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) untargeted metabolomics were used to identify differential metabolites within metabolic pathways. Network pharmacology was applied to mine potential targets of JXCG in the treatment of IS. The identified key targets were validated by constructing an integrated network of metabolomics and network pharmacology and by molecular docking using Cytoscape. The effect of JXCG on IS was evaluated in vivo, and the predicted targets and pathways of JXCG in IS therapy were assessed using immunoblotting. Combining metabolomics and network pharmacology, we identified the therapeutic targets of JXCG for IS. Notably, JXCG lessened neuronal damage and reduced cerebral infarct size in rats with IS. Western blot analysis showed that JXCG upregulated PRKCH and downregulated PRKCE and PRKCQ proteins. Our combined network pharmacology and metabolomics findings showed that JXCG may have therapeutic potential in the treatment of IS by targeting multiple factors and pathways.
Topics: Animals; Metabolomics; Drugs, Chinese Herbal; Network Pharmacology; Ischemic Stroke; Male; Rats; Chromatography, High Pressure Liquid; Rats, Sprague-Dawley; Disease Models, Animal; Brain Ischemia
PubMed: 38958365
DOI: 10.1590/1414-431X2024e13388 -
Ciencia & Saude Coletiva Jul 2024This article explores telecare from telehealth developments and the recent acceleration of the digital health transformation caused by the COVID-19 pandemic, focusing on...
This article explores telecare from telehealth developments and the recent acceleration of the digital health transformation caused by the COVID-19 pandemic, focusing on the Brazilian Unified Health System (SUS). It addresses terminological issues, the scope of actions, the potential use for healthcare, and constraints and contingencies for telecare in Brazil, focusing on teleconsultations and interactions between health professionals and patients. Finally, it presents a set of propositions for the development of telecare policies and practices in Brazil, considering SUS principles, in two central themes: organizational political guidelines and operational propositions to organise services and healthcare delivery. The importance of clarifying the scope and limits of new technologies is highlighted in the attempt to avoid idealizations with proposed solutions to complex health problems. Telecare solutions should be compatible with SUS principles and with the recommended model of care, with the healthcare network coordinated and organised by primary care, ensuring access to health services and integrated and quality healthcare for the Brazilian society.
Topics: Brazil; Telemedicine; Humans; COVID-19; Delivery of Health Care; National Health Programs; Health Services Accessibility; Primary Health Care; Health Policy; Quality of Health Care
PubMed: 38958322
DOI: 10.1590/1413-81232024297.03302024 -
Ciencia & Saude Coletiva Jul 2024Anvisa's public consultation (PC) is the most widely used social participation mechanism in current health regulations, which was based on antagonistic movements: the...
Anvisa's public consultation (PC) is the most widely used social participation mechanism in current health regulations, which was based on antagonistic movements: the democratization of decision-making and State counter-reformation. Starting from the concept of social participation, defined as various actions from society related to public decision-making, which values diversity and the exercise of citizenship, the present article discusses the possibility of PCs configuring a democratic regulation process by considering popular beliefs and colloquial evidence, and promoting the creation of hybrid evidence in an evidence-moderated model. Despite the different interests, the PCs open the door to opportunities for democratic deliberation by society in the search of understanding, where it is expected that the State will make the best decision and justify it. In this sense, the role of evidence in clarifying complex issues is defined as a space where dissent, believed to democratize society, is important in revealing the limits of scientific evidence in an environment of information asymmetry. Finally, this article aims to refute technocracy as an instrument of power in health regulations, thereby achieving the greatest democratic potential of Anvisa's regulations.
Topics: Humans; Democracy; Social Participation; Decision Making; Brazil; Health Policy; Politics
PubMed: 38958319
DOI: 10.1590/1413-81232024297.03172024 -
Acta Cirurgica Brasileira 2024Gene expressions of vascular Endothelial Growth Factor Alpha (VEGFa), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NFkB) and cytokines could be useful...
PURPOSE
Gene expressions of vascular Endothelial Growth Factor Alpha (VEGFa), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NFkB) and cytokines could be useful for identifying potential therapeutic targets to alleviate ischemia-reperfusion injury after liver transplantation. Cytokine gene expressions, VEGFa and NFkB were investigated in a preclinical swine model of liver transplantation.
METHODS
A total of 12 pigs were used as donors and recipients in liver transplantation without venovenous bypass or aortic clamping. NFkB, IL-6, IL-10, VEGFa and Notch1 gene expression were assessed. These samples were collected in two specific times: group 1 (n= 6) - control, samples were collected before recipient's total hepatectomy and group 2 - liver transplantation group (n=6), where the samples were collected one hour after graft reperfusion.
RESULTS
Liver transplantation was successfully performed in all recipients. Liver enzymes were elevated in the transplantation group. NFkB gene expression was significantly decreased in the transplantation group in comparison with the control group (0.62±0.19 versus 0.39±0.08; p= 0.016). No difference was observed between groups Interleucine 6 (IL-6), interleucine 10 (IL-10), VEGFa and Notch homolog 1 (Notch1).
CONCLUSIONS
In this survey a decreased NFkB gene expression in a porcine model of liver transplantation was observed.
Topics: Animals; Liver Transplantation; Vascular Endothelial Growth Factor A; Swine; NF-kappa B; Interleukin-10; Interleukin-6; Reperfusion Injury; Gene Expression; Disease Models, Animal; Receptor, Notch1; Cytokines; Liver; Models, Animal; Male
PubMed: 38958304
DOI: 10.1590/acb392724 -
Brazilian Journal of Biology = Revista... 2024Aestivation and hibernation represent distinct forms of animal quiescence, characterized by physiological changes, including ion composition. Intracellular ion flows...
Aestivation and hibernation represent distinct forms of animal quiescence, characterized by physiological changes, including ion composition. Intracellular ion flows play a pivotal role in eliciting alterations in membrane potential and facilitating cellular communication, while outward K+ currents aid in the restitution and upkeep of the resting membrane potential. This study explores the relationship between inward and outward currents during aestivation in Achatina fulica snails. Specimens were collected near MSUBIT University in Shenzhen and divided into two groups. The first group was kept on a lattice diet, while the second one consisted of aestivating individuals, that were deprived of food and water until a cork-like structure sealed their shells. Recording of current from isolated neurons were conducted using the single-electrode voltage clamp mode with an AxoPatch 200B amplifier. Electrophysiological recordings on pedal ganglia neurons revealed significant differences in the inactivation processes of the Ia and Ikdr components. Alterations in the Ikdr component may inhibit pacemaker activity in pedal ganglion neurons, potentially contributing to locomotion cessation in aestivated animals. The KS current remains unaffected during aestivation. Changes in slow K+ current components could disrupt the resting membrane potential, possibly leading to cell depolarization and influx of Ca2+ and Na+ ions, impacting cell homeostasis. Thus, maintaining the constancy of outward K+ current is essential for cell stability.
Topics: Animals; Snails; Neurons; Membrane Potentials; Estivation; Patch-Clamp Techniques; Potassium; Potassium Channels
PubMed: 38958298
DOI: 10.1590/1519-6984.283314