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1.
Appl Microbiol Biotechnol ; 107(2-3): 897-913, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36625915

RESUMO

The implementation of non-traditional antibacterials is currently one of the most intensively explored areas of modern medical and biological sciences. One of the most promising alternative strategies to combat bacterial infections is the application of lytic phages combined with established and new antibacterials. The presented study investigates the potential of agarose-based biocomposites containing lytic Pseudomonas phages (KT28, KTN4, and LUZ19), cupric ions (Cu2+), strawberry furanone (HDMF), and gentamicin (GE) as antibacterials and anti-virulent compounds for novel wound dressings. Phages (KT28, KTN4, LUZ19, and triple-phage cocktail) alone and in combination with a triple-chemical mixture (Cu + GE + HDMF) when applied as the liquid formulation caused a significant bacterial count reduction and biofilm production inhibition of clinical P. aeruginosa strains. The immobilization in the agarose scaffold significantly impaired the bioavailability and diffusion of phage particles, depending on virion morphology and targeted receptor specificity. The antibacterial potential of chemicals was also reduced by the agarose scaffold. Moreover, the Cu + GE + HDMF mixture impaired the lytic activity of phages depending on viral particles' susceptibility to cupric ion toxicity. Therefore, three administration types were tested and the optimal turned out to be the one separating antibacterials both physically and temporally. Taken together, the additive effect of phages combined with chemicals makes biocomposite a good solution for designing new wound dressings. Nevertheless, the phage utilization should involve an application of aqueous cocktails directly onto the wound, followed by chemicals immobilized in hydrogel dressings which allow for taking advantage of the antibacterial and anti-virulent effects of all components. KEY POINTS: • The immobilization in the agarose impairs the bioavailability of phage particles and the Cu + GE + HDMF mixture. • The cupric ions are toxic to phages and are sequestrated on phage particles and agarose matrix. • The elaborated TIME-SHIFT administration effectively separates antibacterials both physically and temporally.


Assuntos
Bacteriófagos , Infecções por Pseudomonas , Fagos de Pseudomonas , Humanos , Bacteriófagos/fisiologia , Pseudomonas aeruginosa , Sefarose , Fagos de Pseudomonas/fisiologia , Antibacterianos/farmacologia , Infecções por Pseudomonas/microbiologia
2.
Commun Biol ; 6(1): 16, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609683

RESUMO

Microorganisms living at many sites in the human body compose a complex and dynamic community. Accumulating evidence suggests a significant role for microorganisms in cancer, and therapies that incorporate bacteria have been tried in various types of cancer. We previously demonstrated that cupredoxin azurin secreted by the opportunistic pathogen Pseudomonas aeruginosa, enters human cancer cells and induces apoptotic death1-4. However, the physiological interactions between P. aeruginosa and humans and their role in tumor homeostasis are largely unknown. Here, we show that P. aeruginosa upregulated azurin secretion in response to increasing numbers of and proximity to cancer cells. Conversely, cancer cells upregulated aldolase A secretion in response to increasing proximity to P. aeruginosa, which also correlated with enhanced P. aeruginosa adherence to cancer cells. Additionally, we show that cancer patients had detectable P. aeruginosa and azurin in their tumors and exhibited increased overall survival when they did, and that azurin administration reduced tumor growth in transgenic mice. Our results suggest host-bacterial symbiotic mutualism acting as a diverse adjunct to the host defense system via inter-kingdom communication mediated by the evolutionarily conserved proteins azurin and human aldolase A. This improved understanding of the symbiotic relationship of bacteria with humans indicates the potential contribution to tumor homeostasis.


Assuntos
Azurina , Neoplasias , Camundongos , Animais , Humanos , Azurina/genética , Azurina/metabolismo , Azurina/farmacologia , Pseudomonas aeruginosa/metabolismo , Frutose-Bifosfato Aldolase , Neoplasias/genética , Fenômenos Fisiológicos Celulares
3.
BMC Microbiol ; 23(1): 6, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36617571

RESUMO

The control of cellular zinc (Zn) concentrations by dedicated import and export systems is essential for the survival and virulence of Pseudomonas aeruginosa. The transcription of its many Zn transporters is therefore tightly regulated by a known set of transcription factors involved in either the import or the export of Zn. In this work, we show that the Zur protein, a well-known repressor of Zn import, plays a dual role and functions in both import and export processes. In a situation of Zn excess, Zur represses Zn entry, but also activates the transcription of czcR, a positive regulator of the Zn export system. To achieve this, Zur binds at two sites, located by DNA footprinting in the region downstream the czcR transcription start site. In agreement with this regulation, a delay in induction of the efflux system is observed in the absence of Zur and Zn resistance is reduced. The discovery of this regulation highlights a new role of Zur as global regulator of Zn homeostasis in P. aeruginosa disclosing an important link between Zur and zinc export.


Assuntos
Pseudomonas aeruginosa , Zinco , Zinco/metabolismo , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Fatores de Transcrição/genética
4.
Sci Rep ; 13(1): 117, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596850

RESUMO

Phage tail-like bacteriocins (PTLBs) are large proteomic structures similar to the tail phages. These structures function in bacterial competition by making pores in the membrane of their competitors. The PTLBs identified in Pseudomonas aeruginosa are known as R-type and F-type pyocins, which have a narrow spectrum of action. Their specificity is determined by the tail fiber and is closely related to the lipopolysaccharide type of the target competitor strain. In this study, the genome sequences of 32 clinical of P. aeruginosa clinical isolates were analysed to investigate the presence of R-type and F-type pyocins, and one was detected in all strains tested. The pyocins were classified into 4 groups on the basis of the tail fiber and also the homology, phylogeny and structure of the cluster components. A relationship was established between these groups and the sequence type and serotype of the strain of origin and finally the killing spectrum of the representative pyocins was determined showing a variable range of activity between 0 and 37.5%. The findings showed that these pyocins could potentially be used for typing of P. aeruginosa clinical isolates, on the basis of their genomic sequence and cluster structure, and also as antimicrobial agents.


Assuntos
Anti-Infecciosos , Bacteriocinas , Bacteriófagos , Bacteriocinas/genética , Bacteriocinas/farmacologia , Piocinas/farmacologia , Piocinas/química , Pseudomonas aeruginosa , Proteômica , Bacteriófagos/genética
5.
Curr Microbiol ; 80(2): 57, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36588146

RESUMO

Infectious diseases remain one of the major health challenges worldwide due to the problem of antimicrobial resistance. Conventional antimicrobials have the disadvantage that bacteria rapidly acquire resistance to them, so alternatives must be developed to combat antibiotic resistance. Nanotechnology and the repurposing of existing drugs with known biological profiles are new approaches to replacing conventional antimicrobials. In this paper, we have tested the antibacterial activity of sodium acetate (NaA), vitamin C (VC), and zinc oxide nanoparticles (ZnO NPs) against Escherichia coli O157:H7 ATCC 51659 and Pseudomonas aeruginosa ATCC 27853. MIC values for tested compounds ranged from 0.08 to 6.5 mg ml-1, and the effect of combinations and safety profiles against HepG2 cell line of these compounds were also evaluated. At sub-MIC values, tested compounds had a potential antivirulence effect by inhibiting motility and reducing biofilm formation and maturation. Collectively, ZnO NPs and VC are considered safe alternatives to traditional antibiotics that are capable of reducing the development of antibiotic resistance in microbes. Graphical abstract representing the main aim and the final findings of our work. Spread of multidrug-resistant (MDR) bacterial strains created an urge for alternative safe antimicrobial agents. In this work, we found that ZnO NPs and vitamin C are potential candidates that could be used against MDR E.coli and P. aeruginosa.


Assuntos
Anti-Infecciosos , Escherichia coli O157 , Nanopartículas , Óxido de Zinco , Pseudomonas aeruginosa , Óxido de Zinco/farmacologia , Ácido Ascórbico/farmacologia , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Acetatos , Testes de Sensibilidade Microbiana
6.
Sci Rep ; 13(1): 600, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635275

RESUMO

Cystic fibrosis is a hereditary metabolic disorder characterized by impaired traffic of chloride ions and water through membranes of the respiratory and gastrointestinal, that causes inadequate hydration of airway surfaces, dehydrated mucous secretions and a high-sodium chloride sweat. Although the classical presentation of the condition is well known, a better characterization of metabolic alterations related is need. In particular, the metabolic composition alterations of biological fluids may be influence by the disease state and could be captured as putative signature to set targeted therapeutic strategies. A targeted comprehensive mass spectrometry-based platform was employed to dissect the lipid content of saliva samples form CF patients, in order to investigate alterations in the lipid metabolic homeostasis related to the pathology, chronic obstructive pulmonary disease, Pseudomonas Aeruginosa infection, pancreatic insufficiency, liver disfunction and diabetes-related complications.


Assuntos
Fibrose Cística , Humanos , Fibrose Cística/metabolismo , Saliva/metabolismo , Lipidômica , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Lipídeos , Pseudomonas aeruginosa
7.
Proc Natl Acad Sci U S A ; 120(4): e2219679120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36649429

RESUMO

The emergence of multidrug-resistant bacterial pathogens is a growing threat to global public health. Here, we report the development and characterization of a panel of nine-amino acid residue synthetic peptides that display potent antibacterial activity and the ability to disrupt preestablished microbial biofilms. The lead peptide (Peptide K6) showed bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus in culture and in monocultures and mixed biofilms in vitro. Biophysical analysis revealed that Peptide K6 self-assembled into nanostructured micelles that correlated with its strong antibiofilm activity. When surface displayed on the outer membrane protein LamB, two copies of the Peptide K6 were highly bactericidal to Escherichia coli. Peptide K6 rapidly increased the permeability of bacterial cells, and resistance to this toxic peptide occurred less quickly than that to the potent antibiotic gentamicin. Furthermore, we found that Peptide K6 was safe and effective in clearing mixed P. aeruginosa-S. aureus biofilms in a mouse model of persistent infection. Taken together, the properties of Peptide K6 suggest that it is a promising antibiotic candidate and that design of additional short peptides that form micelles represents a worthwhile approach for the development of antimicrobial agents.


Assuntos
Antibacterianos , Coinfecção , Animais , Camundongos , Antibacterianos/farmacologia , Micelas , Staphylococcus aureus , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Biofilmes , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa
8.
Nature ; 613(7943): 324-331, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36599989

RESUMO

Pathogens generate ubiquitous selective pressures and host-pathogen interactions alter social behaviours in many animals1-4. However, very little is known about the neuronal mechanisms underlying pathogen-induced changes in social behaviour. Here we show that in adult Caenorhabditis elegans hermaphrodites, exposure to a bacterial pathogen (Pseudomonas aeruginosa) modulates sensory responses to pheromones by inducing the expression of the chemoreceptor STR-44 to promote mating. Under standard conditions, C. elegans hermaphrodites avoid a mixture of ascaroside pheromones to facilitate dispersal5-13. We find that exposure to the pathogenic Pseudomonas bacteria enables pheromone responses in AWA sensory neurons, which mediate attractive chemotaxis, to suppress the avoidance. Pathogen exposure induces str-44 expression in AWA neurons, a process regulated by a transcription factor zip-5 that also displays a pathogen-induced increase in expression in AWA. STR-44 acts as a pheromone receptor and its function in AWA neurons is required for pathogen-induced AWA pheromone response and suppression of pheromone avoidance. Furthermore, we show that C. elegans hermaphrodites, which reproduce mainly through self-fertilization, increase the rate of mating with males after pathogen exposure and that this increase requires str-44 in AWA neurons. Thus, our results uncover a causal mechanism for pathogen-induced social behaviour plasticity, which can promote genetic diversity and facilitate adaptation of the host animals.


Assuntos
Caenorhabditis elegans , Feromônios , Pseudomonas aeruginosa , Reprodução , Comportamento Sexual Animal , Animais , Feminino , Masculino , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Glicolipídeos/metabolismo , Organismos Hermafroditas/fisiologia , Feromônios/metabolismo , Pseudomonas aeruginosa/patogenicidade , Pseudomonas aeruginosa/fisiologia , Receptores de Feromônios/metabolismo , Reprodução/fisiologia , Células Receptoras Sensoriais/metabolismo
9.
Cells ; 12(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36611992

RESUMO

Pseudomonas aeruginosa is an important Gram-negative opportunistic pathogen which causes many severe acute and chronic infections with high morbidity, and mortality rates as high as 40%. What makes P. aeruginosa a particularly challenging pathogen is its high intrinsic and acquired resistance to many of the available antibiotics. In this review, we review the important acute and chronic infections caused by this pathogen. We next discuss various animal models which have been developed to evaluate P. aeruginosa pathogenesis and assess therapeutics against this pathogen. Next, we review current treatments (antibiotics and vaccines) and provide an overview of their efficacies and their limitations. Finally, we highlight exciting literature on novel antibiotic-free strategies to control P. aeruginosa infections.


Assuntos
Fibrose Cística , Infecções por Pseudomonas , Animais , Pseudomonas aeruginosa , Infecções por Pseudomonas/tratamento farmacológico , Infecção Persistente , Fibrose Cística/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais
10.
Cells ; 12(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36611990

RESUMO

Pseudomonas aeruginosa is one of the most virulent opportunistic Gram-negative bacterial pathogens in humans. It causes many acute and chronic infections with morbidity and mortality rates as high as 40%. P. aeruginosa owes its pathogenic versatility to a large arsenal of cell-associated and secreted virulence factors which enable this pathogen to colonize various niches within hosts and protect it from host innate immune defenses. Induction of cytotoxicity in target host cells is a major virulence strategy for P. aeruginosa during the course of infection. P. aeruginosa has invested heavily in this strategy, as manifested by a plethora of cytotoxins that can induce various forms of cell death in target host cells. In this review, we provide an in-depth review of P. aeruginosa cytotoxins based on their mechanisms of cytotoxicity and the possible consequences of their cytotoxicity on host immune responses.


Assuntos
Infecções por Pseudomonas , Humanos , Virulência , Fatores de Virulência/metabolismo , Citotoxinas , Pseudomonas aeruginosa/metabolismo
11.
Nat Commun ; 14(1): 78, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604442

RESUMO

Carbapenemase-producing Enterobacterales (CPE) are spreading rapidly in hospital settings. Asymptomatic CPE gut colonisation may be associated with dysbiosis and gut-lung axis alterations, which could impact lung infection outcomes. In this study, in male C57BL/6JRj mice colonised by CPE, we characterise the resulting gut dysbiosis, and analyse the lung immune responses and outcomes of subsequent Pseudomonas aeruginosa lung infection. Asymptomatic gut colonisation by CPE leads to a specific gut dysbiosis and increases the severity of P. aeruginosa lung infection through lower numbers of alveolar macrophages and conventional dendritic cells. CPE-associated dysbiosis is characterised by a near disappearance of the Muribaculaceae family and lower levels of short-chain fatty acids. Faecal microbiota transplantation restores immune responses and outcomes of lung infection outcomes, demonstrating the involvement of CPE colonisation-induced gut dysbiosis in altering the immune gut-lung axis, possibly mediated by microbial metabolites such as short-chain fatty acids.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Animais , Camundongos , Masculino , Klebsiella pneumoniae , Disbiose , Camundongos Endogâmicos C57BL , Pulmão , Ácidos Graxos Voláteis
12.
ACS Appl Mater Interfaces ; 15(2): 2781-2791, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36601891

RESUMO

To better understand the impact of biomaterial mechanical properties and growth medium on bacterial adhesion and biofilm formation under flow, we investigated the biofilm formation ability of Pseudomonas aeruginosa in different media on polydimethylsiloxane (PDMS) of different stiffness in real time using a microfluidic platform. P. aeruginosa colonization was recorded with optical microscopy and automated image analysis. The bacterial intracellular level of cyclic diguanylate (c-di-GMP), which regulates biofilm formation, was monitored using the transcription of the putative adhesin gene (cdrA) as a proxy. Contrary to the previous supposition, we revealed that PDMS material stiffness within the tested range has negligible impact on biofilm development and biofilm structures, whereas culture media not only influence the kinetics of biofilm development but also affect the biofilm morphology and structure dramatically. Interestingly, magnesium rather than previously reported calcium was identified here to play a decisive role in the formation of dense P. aeruginosa aggregates and high levels of c-di-GMP. These results demonstrate that although short-term adhesion assays bring valuable insight into bacterial and material interactions, long-term evaluations are essential to better predict overall biofilm outcome. The microfluidic system developed here presents a valuable application potential for studying biofilm development in situ. .


Assuntos
Biofilmes , Pseudomonas aeruginosa , Pseudomonas aeruginosa/genética , Aderência Bacteriana , Meios de Cultura , Proteínas de Bactérias/genética
13.
Methods Enzymol ; 679: 1-32, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36682859

RESUMO

Bacterial pathogens such as Pseudomonas aeruginosa use complex regulatory networks to tailor gene expression patterns to meet complex environmental challenges. P. aeruginosa is capable of causing both acute and chronic persistent infections, each type being characterized by distinct symptoms brought about by distinct sets of virulence mechanisms. The GacS/GacA phosphorelay system sits at the heart of a complex regulatory network that reciprocally governs the expression of virulence factors associated with either acute or chronic infections. A second non-enzymatic signaling cascade involving four proteins, ExsA, ExsC, ExsD, and ExsE is a key player in regulating the expression of the type three secretion system, an essential facilitator of acute infections. Both signaling pathways involve a remarkable array of non-canonical interactions that we sought to characterize. In the following section, we will outline several strategies, we adapted to map protein-protein interfaces and quantify the strength of biomolecular interactions by pairing complex mutational analyses with FRET binding assays and Bacterial-Two-Hybrid assays with appropriate functional assays. In the process, protocols were developed for disrupting large hydrophobic interfaces, deleting entire domains within a protein, and for mapping protein-protein interfaces formed primarily through backbone interactions.


Assuntos
Sistemas de Secreção Bacterianos , Transativadores , Transativadores/química , Sistemas de Secreção Bacterianos/metabolismo , Proteínas Repressoras/química , Proteínas de Bactérias/metabolismo , Pseudomonas aeruginosa/genética , Regulação Bacteriana da Expressão Gênica
14.
Curr Microbiol ; 80(2): 75, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36648563

RESUMO

In this study, bacterial cellulose (BC) impregnated with green synthesized silver nanoparticles (AgNPs) is evaluated as an antimicrobial membrane for wound-healing treatment. Green synthesized silver nanoparticles using Moringa oleifera leaf extract were characterized using UV‒visible spectroscopy, FTIR, X-ray diffraction, and transmission electron microscopy. The results confirmed that the resulted particles were Ag2O and metallic Ag in nanoscale with an average size ranged from 24 to 40 nm. The green synthesized nanoparticles incorporated within both bacterial cellulose and filter paper discs showed excellent antibacterial activities against Staphylococcus aureus ATCC 6538 and Pseudomonas aeruginosa ATCC 9027. There was no significant difference noticed between bacterial cellulose and filter paper holding capacity to nanoparticles and there was lack of interaction between bacterial cellulose and impregnated nanoparticles as elaborated by Fourier transform infrared spectral analyses. Scanning electron microscopy investigation showed major distortions effects of green synthesized silver nanoparticles on bacterial cell morphology.


Assuntos
Nanopartículas Metálicas , Staphylococcus aureus Resistente à Meticilina , Pseudomonas aeruginosa , Nanopartículas Metálicas/química , Staphylococcus aureus , Prata/farmacologia , Celulose , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier , Antibacterianos/farmacologia , Antibacterianos/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Difração de Raios X
15.
Methods Mol Biol ; 2625: 201-216, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36653645

RESUMO

Outer membrane vesicles (OMVs), also called as bacterial membrane vesicles (BMVs), are secreted by many Gram-negative bacterial pathogens. These nanoscale vesicles traffic discrete arrays of virulence factors that can often induce complex pathologies far from the infection sites. The OMVs of P. aeruginosa, often regarded as the gold standard of BMVs are known to traffic a battery of specific small MW alkyl-quinolones (AQs). These AQs function like primordial hormones by modulating intra-species and inter-species bacterial interactions. They can also perform cross-kingdom signaling with the human host and directly exacerbate pathogenesis. The discrete isotopic signatures of AQs enjoy potential in the mass spectrometry-based diagnosis P. aeruginosa infections. Matrix-free laser desorption/ionization mass spectrometry (LDI-MS) presents a robust, cost-effective platform to fit this demand. We describe a LDI-MS system using inert ceramic filters that performs dual role of single-step enrichment of OMVs and matrix-free ionization/identification of AQs in situ.


Assuntos
Quinolonas , Humanos , Pseudomonas aeruginosa , Transdução de Sinais
16.
Microbiol Res ; 268: 127298, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36610273

RESUMO

Pseudomonas aeruginosa is mostly associated with persistent infections and antibiotic resistance as a result of several factors, biofilms one of them. Microorganisms within the polymicrobial biofilm (PMB) reveal various transcriptional profiles and affect each other which might influence their pathogenicity and antibiotic tolerance and subsequent worsening of the biofilm infection. P. aeruginosa within PMB exhibits various behaviours toward other microorganisms, which may enhance or repress the virulence of these microbes. Microbial neighbours, in turn, may affect P. aeruginosa's virulence either positively or negatively. Such interactions among microorganisms lead to emerging persistent and antibiotic-resistant infections. This review highlights the relationship between P. aeruginosa and its microbial neighbours within the PMB in an attempt to better understand the mechanisms of polymicrobial interaction and the correlation between increased exacerbations of infection and the P. aeruginosa-microbe interaction. Researching in the literature that was carried out in vitro either in co-cultures or in the models to simulate the environment at the site of infection suggested that the interplay between P. aeruginosa and other microorganisms is one main reason for the worsening of the infection and which in turn requires a treatment approach different from that followed with P. aeruginosa mono-infection.


Assuntos
Infecções por Pseudomonas , Infecções Estafilocócicas , Humanos , Pseudomonas aeruginosa/genética , Antibacterianos/farmacologia , Interações Microbianas , Biofilmes , Técnicas de Cocultura
17.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674459

RESUMO

The innate immune responses of mammals to microbial infections include strategies based on manipulating the local concentration of metals such as iron (Fe) and zinc (Zn), commonly described as nutritional immunity. To evaluate whether these strategies are also present in zebrafish embryos, we have conducted a series of heart cavity-localized infection experiments with Pseudomonas aeruginosa strains characterized by a different ability to acquire Zn. We have found that, 48 h after infection, the bacterial strains lacking critical components of the Zn importers ZnuABC and ZrmABCD have a reduced colonization capacity compared to the wild-type strain. This observation, together with the finding of a high level of expression of Zur-regulated genes, suggests the existence of antimicrobial mechanisms based on Zn sequestration. However, we have observed that strains lacking such Zn importers have a selective advantage over the wild-type strain in the early stages of infection. Analysis of the expression of the gene that encodes for a Zn efflux pump has revealed that at short times after infection, P. aeruginosa is exposed to high concentrations of Zn. At the same time, zebrafish respond to the infection by activating the expression of the Zn transporters Slc30a1 and Slc30a4, whose mammalian homologs mediate a redistribution of Zn in phagocytes aimed at intoxicating bacteria with a metal excess. These observations indicate that teleosts share similar nutritional immunity mechanisms with higher vertebrates, and confirm the usefulness of the zebrafish model for studying host-pathogen interactions.


Assuntos
Pseudomonas aeruginosa , Peixe-Zebra , Animais , Pseudomonas aeruginosa/fisiologia , Peixe-Zebra/metabolismo , Eucariotos/metabolismo , Transporte de Íons , Zinco/metabolismo , Mamíferos/metabolismo
18.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674469

RESUMO

The synthesis of novel fluoroquinolones, congeners of ciprofloxacin, which was inspired by earlier work on spirocyclic ciprofloxacin, is described. An antibacterial evaluation of the 11 fluoroquinolone compounds synthesized against the ESKAPE panel of pathogens in comparison with ciprofloxacin revealed that the more compact spirocycles in the fluoroquinolone periphery resulted in active compounds, while larger congeners gave compounds that displayed no activity at all. In the active cohort, the level of potency was comparable to that of ciprofloxacin. However, the spectrum of antibacterial activity was quite different, as the new compounds showed no activity against Pseudomonas aeruginosa. Among the prepared and tested compounds, the broadest range of activity (five pathogens of the six in the ESKAPE panel) and the highest level of activity were demonstrated by 1-yclopropyl-7-[8-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)-6-azaspiro[3.4]oct-6-yl]-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is the lead compound nominated for further characterization and development.


Assuntos
Antibacterianos , Ciprofloxacina , Humanos , Ciprofloxacina/farmacologia , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Fluoroquinolonas , Pseudomonas aeruginosa
19.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674518

RESUMO

Chronic wounds have harmful effects on both patients and healthcare systems. Wound chronicity is attributed to an impaired healing process due to several host and local factors that affect healing pathways. The resulting ulcers contain a wide variety of microorganisms that are mostly resistant to antimicrobials and possess the ability to form mono/poly-microbial biofilms. The search for new, effective and safe compounds to handle chronic wounds has come a long way throughout the history of medicine, which has included several studies and trials of conventional treatments. Treatments focus on fighting the microbial colonization that develops in the wound by multidrug resistant pathogens. The development of molecular medicine, especially in antibacterial agents, needs an in vitro model similar to the in vivo chronic wound environment to evaluate the efficacy of antimicrobial agents. The Lubbock chronic wound biofilm (LCWB) model is an in vitro model developed to mimic the pathogen colonization and the biofilm formation of a real chronic wound, and it is suitable to screen the antibacterial activity of innovative compounds. In this review, we focused on the characteristics of chronic wound biofilms and the contribution of the LCWB model both to the study of wound poly-microbial biofilms and as a model for novel treatment strategies.


Assuntos
Anti-Infecciosos , Infecção dos Ferimentos , Humanos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecção Persistente , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , Biofilmes , Pseudomonas aeruginosa
20.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674786

RESUMO

Pseudomonas aeruginosa is an opportunistic pathogen encoding several virulence factors in its genome, which is well-known for its ability to cause severe and life-threatening infections, particularly among cystic fibrosis patients. The organism is also a major cause of nosocomial infections, mainly affecting patients with immune deficiencies and burn wounds, ventilator-assisted patients, and patients affected by other malignancies. The extensively reported emergence of multidrug-resistant (MDR) P. aeruginosa strains poses additional challenges to the management of infections. The aim of this study was to compare the incidence rates of selected virulence-factor-encoding genes and the genotype distribution amongst clinical multidrug-sensitive (MDS) and MDR P. aeruginosa strains. The study involved 74 MDS and 57 MDR P. aeruginosa strains and the following virulence-factor-encoding genes: lasB, plC H, plC N, exoU, nan1, pilA, and pilB. The genotype distribution, with respect to the antimicrobial susceptibility profiles of the strains, was also analyzed. The lasB and plC N genes were present amongst several P. aeruginosa strains, including all the MDR P. aeruginosa, suggesting that their presence might be used as a marker for diagnostic purposes. A wide variety of genotype distributions were observed among the investigated isolates, with the MDS and MDR strains exhibiting, respectively, 18 and 9 distinct profiles. A higher prevalence of genes determining the virulence factors in the MDR strains was observed in this study, but more research is needed on the prevalence and expression levels of these genes in additional MDR strains.


Assuntos
Infecções por Pseudomonas , Fatores de Virulência , Humanos , Fatores de Virulência/genética , Pseudomonas aeruginosa , Virulência/genética , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologia , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/tratamento farmacológico , Genótipo , Testes de Sensibilidade Microbiana
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