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1.
Rev Soc Bras Med Trop ; 53: e20200399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33111915

RESUMO

INTRODUCTION: Pseudomonas aeruginosa is an opportunistic pathogen associated with healthcare-related infections, affecting mainly patients with underlying diseases and immunosuppression. This microorganism has several virulence mechanisms that favour its pathogenesis, including the production of biofilm. This study aimed to analyze the phenotypic production of biofilms, the occurrence of quorum sensing (QS) genes, and the clonal profile of clinical isolates of P. aeruginosa from colonized/infected patients in a tertiary hospital in Recife-PE. METHODS: We obtained 21 isolates that were classified as infection isolates (II), and 10 colonization isolates (CI). The phenotypic analysis for biofilm production was performed quantitatively. The QS genes were detected by specific PCRs, and the clonal profile was assessed using ERIC-PCR. RESULTS: Of the 31 isolates, 58.1 % (18/31) were biofilm producers, of which 70 % (7/10) were CI and classified as weakly adherent; 52.4 % (11/21) of the II produced biofilms, and were classified as weak (38.1 %, (8/21)), moderate (9.5 %, (2/21)), and strongly adherent (4.8 %, (1/21)). All isolates harbored the QS genes analyzed. In the clonal analysis, 26 distinct genetic profiles were identified, highlighting the presence of a clone in four samples, i.e., one infection isolate, and 3 colonization isolates. CONCLUSIONS: The detection of biofilm formation is important in P. aeruginosa in addition to the identification of colonization and infection isolates, especially from complex environments such as ICUs. Further, we define a strategy for monitoring and analyzing P. aeruginosa strains that can potentially cause infections in hospitalized patients.


Assuntos
Infecções por Pseudomonas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Biofilmes , Genótipo , Humanos , Fenótipo , Pseudomonas aeruginosa/genética , Percepção de Quorum/efeitos dos fármacos , Virulência/genética , Fatores de Virulência
2.
PLoS Pathog ; 16(9): e1008867, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925969

RESUMO

Surface attachment, an early step in the colonization of multiple host environments, activates the virulence of the human pathogen P. aeruginosa. However, the downstream toxins that mediate surface-dependent P. aeruginosa virulence remain unclear, as do the signaling pathways that lead to their activation. Here, we demonstrate that alkyl-quinolone (AQ) secondary metabolites are rapidly induced upon surface association and act directly on host cells to cause cytotoxicity. Surface-induced AQ cytotoxicity is independent of other AQ functions like quorum sensing or PQS-specific activities like iron sequestration. We further show that packaging of AQs in outer-membrane vesicles (OMVs) increases their cytotoxicity to host cells but not their ability to stimulate downstream quorum sensing pathways in bacteria. OMVs lacking AQs are significantly less cytotoxic, suggesting these molecules play a role in OMV cytotoxicity, in addition to their previously characterized role in OMV biogenesis. AQ reporters also enabled us to dissect the signal transduction pathways downstream of the two known regulators of surface-dependent virulence, the quorum sensing receptor, LasR, and the putative mechanosensor, PilY1. Specifically, we show that PilY1 regulates surface-induced AQ production by repressing the AlgR-AlgZ two-component system. AlgR then induces RhlR, which can induce the AQ biosynthesis operon under specific conditions. These findings collectively suggest that the induction of AQs upon surface association is both necessary and sufficient to explain surface-induced P. aeruginosa virulence.


Assuntos
Proteínas de Bactérias/metabolismo , Infecções por Pseudomonas/metabolismo , Pseudomonas aeruginosa , Quinolonas/farmacologia , Percepção de Quorum/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Virulência/metabolismo , Células A549 , Animais , Humanos , Camundongos , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade
3.
J Environ Pathol Toxicol Oncol ; 39(2): 125-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749122

RESUMO

Biofilms are a collective of multiple types of bacteria that develop on a variety of surfaces. Biofilm development results in heightened resistance to antibiotics. Quorum sensing plays an important role in biofilm development as it is one of the common communication mechanisms within cells, which balances and stabilizes the environment, when the amount of bacteria increases. Because of the important implications of the roles biofilms play in infectious diseases, it is crucial to investigate natural antibacterial agents that are able to regulate biofilm formation and development. Various studies have suggested that natural plant products have the potential to suppress bacterial growth and exhibit chemopreventive traits in the modulation of biofilm development. In this review, we discuss and collate potential antibiofilm drugs and biological molecules from natural sources, along with their underlying mechanisms of action. In addition, we also discuss the antibiofilm drugs that are currently under clinical trials and highlight their potential future uses.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Infecções/tratamento farmacológico , Extratos Vegetais/farmacologia , Antibacterianos/uso terapêutico , Biofilmes/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno , Humanos , Infecções/microbiologia , Extratos Vegetais/uso terapêutico , Percepção de Quorum/efeitos dos fármacos
4.
PLoS Biol ; 18(8): e3000814, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797039

RESUMO

Plasmid-mediated horizontal gene transfer of antibiotic resistance and virulence in pathogenic bacteria underlies a major public health issue. Understanding how, in the absence of antibiotic-mediated selection, plasmid-bearing cells avoid being outnumbered by plasmid-free cells is key to developing counterstrategies. Here, we quantified the induction of the plasmidial sex pheromone pathway of Enterococcus faecalis to show that the integration of the stimulatory (mate-sensing) and inhibitory (self-sensing) signaling modules from the pCF10 conjugative plasmid provides a precise measure of the recipient-to-donor ratio, agnostic to variations in population size. Such ratiometric control of conjugation favors vertical plasmid transfer under low mating likelihood and allows activation of conjugation functions only under high mating likelihood. We further show that this strategy constitutes a cost-effective investment into mating effort because overstimulation produces unproductive self-aggregation and growth rate reduction. A mathematical model suggests that ratiometric control of conjugation increases plasmid fitness and predicts a robust long-term, stable coexistence of donors and recipients. Our results demonstrate how population-level parameters can control transfer of antibiotic resistance in bacteria, opening the door for biotic control strategies.


Assuntos
Proteínas de Bactérias/genética , Resistência Microbiana a Medicamentos/genética , Enterococcus faecalis/genética , Transferência Genética Horizontal , Feromônios/genética , Percepção de Quorum/efeitos dos fármacos , Antibacterianos/farmacologia , Carga Bacteriana , Proteínas de Bactérias/metabolismo , Conjugação Genética , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Enterococcus faecalis/metabolismo , Expressão Gênica , Aptidão Genética , Modelos Estatísticos , Feromônios/biossíntese , Plasmídeos/química , Plasmídeos/metabolismo , Percepção de Quorum/genética , Virulência
5.
PLoS Biol ; 18(8): e3000805, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810152

RESUMO

Antibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore quencher, and furanone C-30, a quorum sensing [QS] inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant (AtbR) clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most AtbR clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are up-regulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have the potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.


Assuntos
Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Colistina/farmacologia , Furanos/farmacologia , Gálio/farmacologia , Meropeném/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Biossíntese de Proteínas/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Percepção de Quorum/efeitos dos fármacos , Virulência
6.
Int J Food Microbiol ; 331: 108732, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-32521374

RESUMO

The present study aimed to evaluate the anti-quorum sensing (anti-QS) and anti-proteolytic potentials of tarragon essential oil (TEO) and its major compounds against food-associated Pseudomonas spp. The activities were verified by in vitro, in silico and in situ approaches. In this work, methyl eugenol (ME)- and ß-phellandrene (ß-PH)-rich TEO was investigated. TEO at subMIC increased the percentage of saturated fatty acids in the bacterial membranes (from 7 to 22%) and exhibited anti-quorum sensing via decreasing the efficiency of QS autoinducer synthesis [3-oxo-C12-HSL (from 2.028 µg/mL to

Assuntos
Artemisia/química , Óleos Voláteis/farmacologia , Proteólise/efeitos dos fármacos , Pseudomonas/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , 4-Butirolactona/análogos & derivados , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Simulação por Computador , Peixes/microbiologia , Homosserina/análogos & derivados , Homosserina/isolamento & purificação , Homosserina/farmacologia , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Pseudomonas/isolamento & purificação
7.
Biofouling ; 36(3): 351-367, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32401555

RESUMO

Pseudomonas aeruginosa and Serratia marcescens are prominent members belonging to the group of ESKAPE pathogens responsible for Urinary Tract Infections (UTI) and nosocomial infections. Both the pathogens regulate several virulence factors, including biofilm formation through quorum sensing (QS), an intercellular communication mechanism. The present study describes the anti-biofilm and QS quenching effect of thiazolinyl-picolinamide based palladium(II) complexes against P. aeruginosa and S. marcescens. Palladium(II) complexes showed quorum sensing inhibitory potential in inhibiting swarming motility behaviour, pyocyanin production and other QS mediated virulence factors in both P. aeruginosa and S. marcescens. In addition, the establishment of biofilms was prevented on palladium (II) coated catheters. Overall, the present study demonstrates that thiazolinyl-picolinamide based palladium (II) complexes will be a promising strategy to combat device-mediated UTI infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Paládio/farmacologia , Ácidos Picolínicos/química , Tiazóis/química , Cateteres Urinários/microbiologia , Antibacterianos/química , Antibacterianos/toxicidade , Biofilmes/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Infecção Hospitalar/prevenção & controle , Humanos , Células MCF-7 , Paládio/química , Paládio/toxicidade , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Piocianina/metabolismo , Percepção de Quorum/efeitos dos fármacos , Serratia marcescens/efeitos dos fármacos , Serratia marcescens/metabolismo , Infecções Urinárias/microbiologia , Infecções Urinárias/prevenção & controle , Virulência , Fatores de Virulência/metabolismo
8.
Mar Drugs ; 18(4)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290259

RESUMO

Pseudomonas aeruginosa is an opportunistic pathogen using virulence factors and biofilm regulated by quorum sensing (QS) systems to infect patients and protect itself from environmental stress and antibiotics. Interfering with QS systems is a novel approach to combat P. aeruginosa infections without killing the bacteria, meaning that it is much harder for bacteria to develop drug resistance. A marine fungus Cladosporium sp. Z148 with anti-QS activity was obtained from Jiaozhou Bay, China. Cladodionen, a novel QS inhibitor, was isolated from the extracts of this fungus. Cladodionen had a better inhibitory effect than pyocyanin on the production of elastase and rhamnolipid. It also inhibited biofilm formation and motilities. The mRNA expressions of QS-related genes, including receptor proteins (lasR, rhlR and pqsR), autoinducer synthases (lasI, rhlI and pqsA) and virulence factors (lasB and rhlA) were down-regulated by cladodionen. Molecular docking analysis showed that cladodionen had better binding affinity to LasR and PqsR than natural ligands. Moreover, the binding affinity of cladodionen to LasR was higher than to PqsR. Cladodionen exhibits potential as a QS inhibitor against P. aeruginosa, and its structure-activity relationships should be further studied to illustrate the mode of action, optimize its structure and improve anti-QS activity.


Assuntos
Antibacterianos/química , Organismos Aquáticos , Cladosporium , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Baías , China , Pseudomonas aeruginosa/patogenicidade , Percepção de Quorum/efeitos dos fármacos
9.
PLoS One ; 15(4): e0231625, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298346

RESUMO

BACKGROUND: Serratia marcescens is an emerging pathogen that causes a variety of health care associated infections. S. marcescens is equipped with an arsenal of virulence factors such as biofilm formation, swimming and swarming motilities, prodigiosin, protease and others which enable it to initiate and cause the infection. These virulence factors are orchestrated under the umbrella of an intercellular communication system named Quorum sensing (QS). QS allows bacterial population to synchronize the expression of virulence genes upon detection of a chemical signaling molecule. Targeting bacterial virulence is a promising approach to attenuate bacteria and enhances the ability of immune system to eradicate the bacterial infection. Drug repurposing is an advantageous strategy that confers new applications for drugs outside the scope of their original medical use. This promising strategy offers the use of safe approved compounds, which potentially lowers the costs and shortens the time than that needed for development of new drugs. Sitagliptin is dipeptidyl peptidase-4 (DPP-4) inhibitor, is used to treat diabetes mellitus type II as it increases the production of insulin and decreasing the production of glucagon by the pancreas. We aimed in this study to repurpose sitagliptin, investigating the anti-virulence activities of sitagliptin on S. marcescens. METHODS: The effect of sub-inhibitory concentrations of sitagliptin on virulence factors; protease, prodigiosin, biofilm formation, swimming and swarming motilities was estimated phenotypically. The qRT-PCR was used to show the effect of sitagliptin on the expression of QS-regulated virulence genes. The in-vivo protective activity of sitagliptin on S. marcescens pathogenesis was evaluated on mice. RESULTS: Sitagliptin (1 mg/ml) significantly reduced the biofilm formation, swimming and swarming motilities, prodigiosin and protease. The qRT-PCR confirmed the effect on virulence as shown by down regulating the expression of fimA, fimC, flhC, flhD, bsmB, rssB, rsmA, pigP, and shlA genes. Moreover, the in-vivo findings showed the efficient ability of sitagliptin to weaken S. marcescens pathogenesis. CONCLUSION: Sitagliptin is a promising anti-virulence agent against S. marcescens that may be beneficial in the control of healthcare associated infections caused by S. marcescens.


Assuntos
Antibacterianos/farmacologia , Reposicionamento de Medicamentos , Hipoglicemiantes/farmacologia , Serratia marcescens/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Virulência/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Humanos , Percepção de Quorum/efeitos dos fármacos , Infecções por Serratia/tratamento farmacológico , Infecções por Serratia/microbiologia , Serratia marcescens/patogenicidade , Serratia marcescens/fisiologia
10.
PLoS One ; 15(4): e0230423, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236115

RESUMO

Campylobacter jejuni is one of the most prevalent causes of bacterial gastroenteritis worldwide, and it is largely associated with consumption of contaminated poultry. Current Campylobacter control measures at the poultry production level remain insufficient, and hence there is the need for alternative control strategies. We evaluated the potential of the monoterpene (-)-α-pinene for control of C. jejuni in poultry. The antibacterial and resistance-modulatory activities of (-)-α-pinene were also determined against 57 C. jejuni strains. In addition, the anti-quorum-sensing activity of (-)-α-pinene against C. jejuni NCTC 11168 was determined for three subinhibitory concentrations (125, 62.5, 31.25 mg/L) over three incubation times using an autoinducer-2 bioassay based on Vibrio harveyi BB170 bioluminescence measurements. The effects of a subinhibitory concentration of (-)-α-pinene (250 mg/L) on survival of C. jejuni, and in combination with enrofloxacin on fluoroquinolone resistance development in C. jejuni, were determined in a broiler chicken model, by addition of (-)-α-pinene to the broiler water supply. The reduction of C. jejuni numbers by (-)-α-pinene was further determined in broiler chickens that were colonized with either fluoroquinolone-susceptible or -resistant strains, by direct gavage treatment. We observed weak in vitro antimicrobial activity for (-)-α-pinene alone (MIC >500 mg/L), but strong potentiating effects on antibiotics erythromycin and ciprofloxacin against different Campylobacter strains (>512 fold change). After 24 h of treatment of C. jejuni with (-)-α-pinene, its quorum-sensing signaling was reduced by >80% compared to the untreated control. When given in the drinking water, (-)-α-pinene did not show any significant inhibitory effects on the level of C. jejuni in the colonized chickens, and did not reduce fluoroquinolone resistance development in combination with enrofloxacin. Conversely, when (-)-α-pinene was administered by direct gavage, it significantly reduced the number of fluoroquinolone susceptible C. jejuni in the colonized broiler chickens. These results demonstrate that (-)-α-pinene modulates quorum-sensing in Campylobacter, potentiates antibiotics against different Campylobacter strains, and reduces Campylobacter colonization in broiler chickens.


Assuntos
Antibacterianos/farmacologia , Monoterpenos Bicíclicos/farmacologia , Campylobacter jejuni/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Monoterpenos Bicíclicos/uso terapêutico , Infecções por Campylobacter/patologia , Infecções por Campylobacter/prevenção & controle , Campylobacter jejuni/fisiologia , Ceco/microbiologia , Galinhas , Ciprofloxacino/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Eritromicina/farmacologia , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Testes de Sensibilidade Microbiana , Doenças das Aves Domésticas/patologia , Doenças das Aves Domésticas/prevenção & controle
11.
J Med Microbiol ; 69(5): 767-780, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32320374

RESUMO

Introduction. An important factor for delayed healing of chronic wounds is the presence of bacteria. Quorum sensing (QS), a cell density-dependent signalling system, controls the production of many virulence factors and biofilm formation in Pseudomonas aeruginosa.Aim. Inhibition by sodium salicylate (NaSa) of QS-regulated virulence expression was evaluated in QS-characterized clinical wound isolates of P. aeruginosa, cultured in serum-containing medium.Methodology. Fourteen clinical P. aeruginosa strains from chronic wounds were evaluated for the production of QS signals and virulence factors. Inhibition of QS by NaSa in P. aeruginosa clinical strains, wild-type PAO1 and QS reporter strains was evaluated using in vitro assays for the production of biofilm, pyocyanin, siderophores, alkaline protease, elastase and stapholytic protease.Results. Six clinical strains secreted several QS-associated virulence factors and signal molecules and two were negative for all factors. Sub-inhibitory concentrations of NaSa downregulated the expression of the QS-related genes lasB, rhlA and pqsA and reduced the secretion of several virulence factors in PAO1 and clinical strains cultured in serum. Compared to serum-free media, the presence of serum increased the expression of QS genes and production of siderophores and pyocyanin but decreased biofilm formation.Conclusions. Pseudomonas aeruginosa from chronic wound infections showed different virulence properties. While very few strains showed no QS activity, approximately half were highly virulent and produced QS signals, suggesting that the targeting of QS is a viable and relevant strategy for infection control. NaSa showed activity as a QS-inhibitor by lowering the virulence phenotypes and QS signals at both transcriptional and extracellular levels.


Assuntos
Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum/efeitos dos fármacos , Salicilato de Sódio/farmacologia , Doença Crônica , Humanos , Pseudomonas aeruginosa/isolamento & purificação , Virulência/efeitos dos fármacos , Fatores de Virulência/genética
12.
Mol Biol (Mosk) ; 54(1): 153-163, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163399

RESUMO

Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to "not kill, but disarm" the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using AutoDock Vina, rDock, LeDock for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro/in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Simulação por Computador , Flavonas/química , Flavonas/farmacologia , Pseudomonas aeruginosa , Percepção de Quorum/efeitos dos fármacos , Transativadores/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos
13.
Mar Drugs ; 18(2)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012662

RESUMO

Previously, we reported that the ethanol extract from red seaweed Gracilaria fisheri effectively decreased biofilm formation of Vibrio harveyi. In this study, the anti-biofilm active compounds in the ethanol extract were isolated and their structures identified. The anti-biofilm fractionation assay for minimum inhibitory concentration (MIC) produced two fractions which possessed maximal inhibitory activities toward the biofilm formation of V. harveyi strains 1114 and BAA 1116. Following chromatographic separation of the bioactive fractions, two pure compounds were isolated, and their structures were elucidated using FTIR, NMR, and HR-TOF-MS. The compounds were N-benzyl cinnamamide and α-resorcylic acid. The in vitro activity assay demonstrated that both compounds inhibited the biofilm formation of V. harveyi and possessed the anti-quorum sensing activity by interfering with the bioluminescence of the bacteria. However, the N-benzyl cinnamamide was more potent than α-resorcylic acid with a 10-fold lesser MIC. The present study reveals the beneficial property of the N-benzyl cinnamamide from the ethanol extract as a lead anti-microbial drug against V. harveyi.


Assuntos
Antibacterianos/farmacologia , Cinamatos/farmacologia , Gracilaria , Percepção de Quorum/efeitos dos fármacos , Hidroxibenzoatos , Resorcinóis , Alga Marinha/efeitos dos fármacos , Vibrio/efeitos dos fármacos , Vibrio/fisiologia
14.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-32020908

RESUMO

With the emergence of multidrug-resistant 'superbug', conventional treatments become obsolete. Quorum quenching (QQ), enzyme-dependent alteration of quorum sensing (QS), is now considered as a promising antimicrobial therapy because of its potentiality to impede virulence gene expression without resulting in growth inhibition and antibiotic resistance. In our study, we intended to compare between two major QQ enzyme groups (i.e., AHL lactonases and AHL acylases) in terms of their structural and functional aspects. The amino acid composition-based principal component analysis (PCA) suggested that probably there is no structural and functional overlapping between the two groups of enzymes as well as within the lactonase enzymes but the acylases may functionally be affected by one another. In subcellular localization analysis, we also found that most lactonases are cytoplasmic while acylases are periplasmic. Investigation on the secondary structural features showed random coil dominates over alpha-helix and beta-sheet in all evaluated enzymes. For structural comparison, the tertiary structures of the selected proteins were modelled and submitted to the PMDB database (Accession ID: PM0081007 to PM0081018). Interestingly, sequence alignment revealed the presence of several conserved domains important for functions in both protein groups. In addition, three amino acid residues, namely aspartic acid, histidine, and isoleucine, were common in the active sites of all protein models while most frequent ligands were found to be 3C7, FEO, and PAC. Importantly, binding interactions of predicted ligands were similar to that of native QS signal molecules. Furthermore, hydrogen bonds analysis suggested six proteins are more stable than others. We believe that the knowledge of this comparative study could be useful for further research in the development of QSbased universal antibacterial strategies.


Assuntos
Acil-Butirolactonas/metabolismo , Amidoidrolases/farmacologia , Hidrolases de Éster Carboxílico/farmacologia , Percepção de Quorum/efeitos dos fármacos , Química Computacional , Filogenia
15.
Mar Drugs ; 18(2)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093216

RESUMO

Marine sponges, a well-documented prolific source of natural products, harbor highly diverse microbial communities. Their extracts were previously shown to contain quorum sensing (QS) signal molecules of the N-acyl homoserine lactone (AHL) type, known to orchestrate bacterial gene regulation. Some bacteria and eukaryotic organisms are known to produce molecules that can interfere with QS signaling, thus affecting microbial genetic regulation and function. In the present study, we established the production of both QS signal molecules as well as QS inhibitory (QSI) molecules in the sponge species Sarcotragus spinosulus. A total of eighteen saturated acyl chain AHLs were identified along with six unsaturated acyl chain AHLs. Bioassay-guided purification led to the isolation of two brominated metabolites with QSI activity. The structures of these compounds were elucidated by comparative spectral analysis of 1HNMR and HR-MS data and were identified as 3-bromo-4-methoxyphenethylamine (1) and 5,6-dibromo-N,N-dimethyltryptamine (2). The QSI activity of compounds 1 and 2 was evaluated using reporter gene assays for long- and short-chain AHL signals (Escherichia coli pSB1075 and E. coli pSB401, respectively). QSI activity was further confirmed by measuring dose-dependent inhibition of proteolytic activity and pyocyanin production in Pseudomonas aeruginosa PAO1. The obtained results show the coexistence of QS and QSI in S. spinosulus, a complex signal network that may mediate the orchestrated function of the microbiome within the sponge holobiont.


Assuntos
Escherichia coli/efeitos dos fármacos , Poríferos/metabolismo , Poríferos/microbiologia , Percepção de Quorum/efeitos dos fármacos , Animais , Escherichia coli/fisiologia , Medições Luminescentes , Peptídeo Hidrolases/química , Peptídeo Hidrolases/farmacologia , Filogenia , Poríferos/genética , Piocianina/química , Piocianina/farmacologia , Fatores de Virulência
16.
J Med Microbiol ; 69(2): 195-206, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31971503

RESUMO

Micro-organisms use quorum sensing (QS), a cell density-dependent process, to communicate. This QS mode of interchange leads to the production of a variety of virulence factors, co-ordination of complex bacterial behaviours, such as swarming motility, degradation of host tissue and biofilm formation. QS is implicated in numerous human infections and consequently researchers have sought ways of effectively inhibiting the process in pathogenic bacteria. Two decades ago, furanones were the first class of chemical compounds identified as Pseudomonas aeruginosa QS inhibitors (QSIs). P. aeruginosa is a ubiquitous organism, capable of causing a wide range of infections in humans, including eye and ear infections, wound infections and potentially fatal bacteraemia and thus novel treatments against this organism are greatly needed. This review provides a brief background on QS and the use of furanones as QSIs. Based on the effectiveness of action, both in vivo and in vitro, we will explore the use of furanones as potential antimicrobial therapeutics and conclude with open questions.


Assuntos
Antibacterianos/administração & dosagem , Furanos/administração & dosagem , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Animais , Antibacterianos/química , Furanos/química , Humanos , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/fisiologia
17.
J Basic Microbiol ; 60(3): 207-215, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31960983

RESUMO

The treatment of Helicobacter pylori usually fails due to their ability to form biofilms and resistance to antibiotics. This might potentially lead to gastric carcinoma and mucosa-associated lymphoid tissue lymphoma. In the present study, we elucidate the potential role of N-acylhomoserine lactonase stabilized silver nanoparticles (AiiA-AgNPs) in treating biofilms produced by H. pylori. AiiA-AgNPs inhibited quorum sensing (QS) by degradation of QS molecules, thereby reducing biofilm formation, urease production, and altering cell surface hydrophobicity of H. pylori. AiiA-AgNPs showed no cytotoxic effects on RAW 264.7 macrophages at the effective concentration (1-5 µM) of antibiofilm activity. In addition, AiiA-AgNP in high concentration (80-100 µM) exhibited cytotoxicity against HCT-15 carcinoma cells, depicting its therapeutic role in treating cancer.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Hidrolases de Éster Carboxílico/farmacologia , Helicobacter pylori/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Prata/farmacologia , Animais , Antibacterianos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Biofilmes/crescimento & desenvolvimento , Hidrolases de Éster Carboxílico/química , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Helicobacter pylori/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Nanopartículas Metálicas/química , Camundongos , Células RAW 264.7 , Prata/química , Urease/metabolismo
18.
Proc Natl Acad Sci U S A ; 117(3): 1689-1699, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31915298

RESUMO

Streptococcus pneumoniae is an opportunistic human pathogen that utilizes the competence regulon, a quorum-sensing circuitry, to acquire antibiotic resistance genes and initiate its attack on the human host. Interception of the competence regulon can therefore be utilized to study S. pneumoniae cell-cell communication and behavioral changes, as well as attenuate S. pneumoniae infectivity. Herein we report the design and synthesis of cyclic dominant negative competence-stimulating peptide (dnCSP) analogs capable of intercepting the competence regulon in both S. pneumoniae specificity groups with activities at the low nanomolar range. Structural analysis of lead analogs provided important insights as to the molecular mechanism that drives CSP receptor binding and revealed that the pan-group cyclic CSPs exhibit a chimeric hydrophobic patch conformation that resembles the hydrophobic patches required for both ComD1 and ComD2 binding. Moreover, the lead cyclic dnCSP, CSP1-E1A-cyc(Dap6E10), was found to possess superior pharmacological properties, including improved resistance to enzymatic degradation, while remaining nontoxic. Lastly, CSP1-E1A-cyc(Dap6E10) was capable of attenuating mouse mortality during acute pneumonia caused by both group 1 and group 2 S. pneumoniae strains. This cyclic pan-group dnCSP is therefore a promising drug lead scaffold against S. pneumoniae infections that could be administered individually or utilized in combination therapy to augment the effects of current antimicrobial agents.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/farmacologia , Percepção de Quorum/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Infecções Pneumocócicas/tratamento farmacológico , Ligação Proteica , Regulon/efeitos dos fármacos
19.
Appl Microbiol Biotechnol ; 104(5): 1871-1881, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927762

RESUMO

Quorum sensing (QS) is a mechanism that enables microbial communication. It is based on the constant secretion of signaling molecules to the environment. The main role of QS is the regulation of vital processes in the cell such as virulence factor production or biofilm formation. Due to still growing bacterial resistance to antibiotics that have been overused, it is necessary to search for alternative antimicrobial therapies. One of them is quorum quenching (QQ) that disrupts microbial communication. QQ-driving molecules can decrease or even completely inhibit the production of virulence factors (including biofilm formation). There are few QQ strategies that comprise the use of the structural analogues of QS receptor autoinductors (AI). They may be found in nature or be designed and synthesized via chemical engineering. Many of the characterized QQ molecules are enzymes with the ability to degrade signaling molecules. They can also impede cellular signaling cascades. There are different techniques used for testing QS/QQ, including chromatography-mass spectroscopy, bioluminescence, chemiluminescence, fluorescence, electrochemistry, and colorimetry. They all enable qualitative and quantitative measurements of QS/QQ molecules. This article gathers the information about the mechanisms of QS and QQ, and their effect on microbial biofilm formation. Basic methods used to study QS/QQ, as well as the medical and biotechnological applications of QQ, are also described. Basis research methods are also described as well as medical and biotechnological application.


Assuntos
Biofilmes , Percepção de Quorum , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Fenômenos Fisiológicos Bacterianos/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Percepção de Quorum/efeitos dos fármacos , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
20.
Mar Drugs ; 18(1)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963874

RESUMO

Five new perylenequinone derivatives, altertoxins VIII-XII (1-5), as well as one known compound cladosporol I (6), were isolated from the fermentation broth of the marine-derived fungus Cladosporium sp. KFD33 from a blood cockle from Haikou Bay, China. Their structures were determined based on spectroscopic methods and ECD spectra analysis along with quantum ECD calculations. Compounds 1-6 exhibited quorum sensing inhibitory activities against Chromobacterium violaceum CV026 with MIC values of 30, 30, 20, 30, 20 and 30 µg/well, respectively.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Cladosporium/química , Perileno/análogos & derivados , Quinonas/química , Percepção de Quorum/efeitos dos fármacos , China , Testes de Sensibilidade Microbiana/métodos , Naftalenos/química , Naftalenos/farmacologia , Perileno/química , Perileno/farmacologia , Quinonas/farmacologia
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