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1.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33739918

RESUMO

Introduction. Carbapenem resistance in Acinetobacter baumannii (A. baumannii) is an emerging global threat.Gap statement. The adaptation strategies of A. baumannii for this emergence as a nosocomial pathogen has been less studied.Aim. This prospective study analysed a sustained outbreak of carbapenem resistant Acinetobacter baumannii (CRAB) in the intensive care unit (ICU) with reference to antimicrobial resistance and virulence in the colonizing and pathogenic isolates under carbapenem stress.Results. The CRAB isolates from initial and sustained outbreak were found harbouring multiple carbapenemase genes. These genes included bla OXA-23 ,bla IMP, bla VIM and bla NDM. From NICU environment three phenotypically carbapenem susceptible isolates were found carrying bla OXA-23, bla IMP, bla VIM genes. Prior imipenem therapy was one of the risk factors (P=0.0016). The outbreak was polyclonal. Under imipenem stress, outbreak isolates showed no loss of carbapenemase genes against stress free conditions (23.7±1.33 days). Biofilm formation increased with imipenem concentration, with outbreak isolates producing highest biomass. While the pathogens showed a slow growth rate on imipenem exposure, the colonisers grew rapidly (P <0.0001).Methods. Sustained outbreak of CRAB was identified in the ICU (July 2015 to December 2017). Risk factors for acquisition of CRAB was studied. A. baumannii isolates were also collected from the environments of ICU and neonatal ICU (NICU) and blood cultures of septic neonates. Isolates were characterized based on antimicrobial susceptibility, genetic profile, integrons carriage and clonality. Biofilm formation and growth kinetics were studied under varying carbapenem stress.Conclusion. Intense carbapenem exposure in the ICU facilitates persistence of CRAB by several adaptations causing sustained outbreaks.


Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/fisiologia , Adaptação Fisiológica , Carbapenêmicos/farmacologia , Infecção Hospitalar/microbiologia , Surtos de Doenças , Farmacorresistência Bacteriana Múltipla/fisiologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/epidemiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Carbapenêmicos/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/genética , Microbiologia Ambiental , Feminino , Genes Bacterianos , Humanos , Imipenem/farmacologia , Imipenem/uso terapêutico , Integrons/genética , Unidades de Terapia Intensiva , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Virulência , beta-Lactamases/genética , beta-Lactamases/metabolismo
2.
Molecules ; 26(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672753

RESUMO

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24-31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4-20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Quinolonas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/química , Staphylococcus aureus/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos
3.
BMC Infect Dis ; 21(1): 266, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731026

RESUMO

BACKGROUND: Chlorhexidine is a widely used disinfectant in clinical settings and a broad-spectrum antimicrobial agent effective against aerobic and anaerobic bacteria. However, disinfectant resistant or non-susceptible bacteria, including antibiotic-resistant Acinetobacter baumannii, have been found. This study aimed to develop a new technique to prevent and control A. baumannii infection in the hospital setting. METHODS: Chlorhexidine combined with minocycline, doxycycline, meropenem, imipenem, levofloxacin and ciprofloxacin were tested against the 30 multidrug-resistant and extremely drug-resistant A. baumannii clinical isolates. The checkerboard test was used to calculate the fractional inhibitory concentration index according to the minimum inhibitory concentration value for chlorhexidine combined with antibiotics. RESULTS: The combination of chlorhexidine with minocycline, doxycycline, meropenem, or ciprofloxacin showed synergistic responses in all clinical isolates, and more than 50% of isolates showed FICI ≤0.5. However, chlorhexidine together with imipenem or levofloxacin showed indifferent responses in 10% and 3.33% clinical isolates, respectively. In all tests, combinations of chlorhexidine with each of the above six antibiotics showed synergistic and additive effects, and inhibited the clinical isolates. CONCLUSIONS: We concluded that, chlorhexidine combined with antibiotics could be used to control the risk of infection with A. baumannii.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Clorexidina/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Acinetobacter baumannii/fisiologia , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana
4.
ACS Appl Mater Interfaces ; 13(6): 7070-7079, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33544596

RESUMO

The anion-exchange capacity of the cell-wall sulfated polysaccharide of the red microalga Porphyridium sp. can be exploited for the complexation of metal ions (e.g., Cu, Zn, Ag) to produce novel materials with new bioactivities. In this study, we investigated this algal polysaccharide as a platform for the incorporation of copper as Cu2O. Chemical and rheological characterization of the Cu2O-polysaccharide complex showed that the copper is covalently bound to the polysaccharide and that the complex exhibits higher viscosity and conductivity than the native polysaccharide. Examination of the complex's inhibitory activity against the bacteria Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Bacillus subtilis and the fungus Candida albicans revealed a relatively high antimicrobial activity, especially against C. albicans (92% growth inhibition) as compared to the polysaccharide and to Cu2O alone. The antibiofilm activity was also found against P. aeruginosa PA14 and C. albicans biofilms. An atomic force microscopy examination of the surface morphology of the complex revealed needle-like structures (spikes), approximately 10 nm thick, protruding from the complex surface to a maximum height of 1000 nm, at a density of about 5000/µm2, which were not detected in the native polysaccharide. It seems that the spikes on the surface of the Cu2O-polysaccharide complex are responsible for the antimicrobial activities of the complex, that is, for disruption of microbial membrane permeability, leading to cell death. The study thus indicates that the superior qualities of the novel material formed by complexion of Cu2O to the polysaccharide should be studied further for various biotechnological applications.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Cobre/farmacologia , Microalgas/química , Polissacarídeos/farmacologia , Sulfatos/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cobre/química , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Polissacarídeos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Sulfatos/química , Propriedades de Superfície
5.
ACS Appl Mater Interfaces ; 13(7): 8082-8094, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33570927

RESUMO

Antibiotic-resistant bacteria are a significant and growing threat to human health. Recently, two-dimensional (2D) nanomaterials have shown antimicrobial activity and have the potential to be used as new approaches to treating antibiotic resistant bacteria. In this Research Article, we exfoliate transition metal dichalcogenide (TMDC) nanosheets using synthetic single-stranded DNA (ssDNA) sequences, and demonstrate the broad-spectrum antibacterial activity of MoSe2 encapsulated by the T20 ssDNA sequence in eliminating several multidrug-resistant (MDR) bacteria. The MoSe2/T20 is able to eradicate Gram-positive Escherichia coli and Gram-positive Staphylococcus aureus at much lower concentrations than graphene-based nanomaterials. Eradication of MDR strains of methicillin-resistant S. aureus (MRSA), Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii are shown to occur at at 75 µg mL-1 concentration of MoSe2/T20, and E. coli at 150 µg mL-1. Molecular dynamics simulations show that the thymine bases in the T20 sequence lie flat on the MoSe2 surface and can, thus, form a very good conformal coating and allow the MoSe2 to act as a sharp nanoknife. Electron microscopy shows the MoSe2 nanosheets cutting through the cell membranes, resulting in significant cellular damage and the formation of interior voids. Further assays show the change in membrane potential and reactive oxygen species (ROS) formation as mechanisms of antimicrobial activity of MoSe2/T20. The cellular death pathways are also examined by mRNA expression. This work shows that biocompatible TMDCs, specifically MoSe2/T20, is a potent antimicrobial agent against MDR bacteria and has potential for clinical settings.


Assuntos
Antibacterianos/farmacologia , Calcogênios/farmacologia , DNA de Cadeia Simples/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Metais Pesados/farmacologia , Células A549 , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/química , Cápsulas/química , Cápsulas/farmacologia , Calcogênios/química , DNA de Cadeia Simples/síntese química , Enterococcus faecalis/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Metais Pesados/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Pseudomonas aeruginosa/efeitos dos fármacos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície
6.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429999

RESUMO

Online Chemical Modeling Environment (OCHEM) was used for QSAR analysis of a set of ionic liquids (ILs) tested against multi-drug resistant (MDR) clinical isolate Acinetobacter baumannii and Staphylococcus aureus strains. The predictive accuracy of regression models has coefficient of determination q2 = 0.66 - 0.79 with cross-validation and independent test sets. The models were used to screen a virtual chemical library of ILs, which was designed with targeted activity against MDR Acinetobacter baumannii and Staphylococcus aureus strains. Seven most promising ILs were selected, synthesized, and tested. Three ILs showed high activity against both these MDR clinical isolates.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Imidazóis/química , Piridinas/química , Acinetobacter baumannii/patogenicidade , Infecções Bacterianas/microbiologia , Resistência a Múltiplos Medicamentos , Humanos , Imidazóis/síntese química , Líquidos Iônicos/síntese química , Líquidos Iônicos/química , Piridinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Relação Estrutura-Atividade
7.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33430070

RESUMO

The nosocomial opportunistic Gram-negative bacterial pathogen Acinetobacter baumannii is resistant to multiple antimicrobial agents and an emerging global health problem. The polymyxin antibiotic colistin, targeting the negatively charged lipid A component of the lipopolysaccharide on the bacterial cell surface, is often considered as the last-resort treatment, but resistance to colistin is unfortunately increasing worldwide. Notably, colistin-susceptible A. baumannii can also develop a colistin dependence after exposure to this drug in vitro. Colistin dependence might represent a stepping stone to resistance also in vivo. However, the mechanisms are far from clear. To address this issue, we combined proteogenomics, high-resolution microscopy, and lipid profiling to characterize and compare A. baumannii colistin-susceptible clinical isolate (Ab-S) of to its colistin-dependent subpopulation (Ab-D) obtained after subsequent passages in moderate colistin concentrations. Incidentally, in the colistin-dependent subpopulation the lpxA gene was disrupted by insertion of ISAjo2, the lipid A biosynthesis terminated, and Ab-D cells displayed a lipooligosaccharide (LOS)-deficient phenotype. Moreover, both mlaD and pldA genes were perturbed by insertions of ISAjo2 and ISAba13, and LOS-deficient bacteria displayed a capsule with decreased thickness as well as other surface imperfections. The major changes in relative protein abundance levels were detected in type 6 secretion system (T6SS) components, the resistance-nodulation-division (RND)-type efflux pumps, and in proteins involved in maintenance of outer membrane asymmetry. These findings suggest that colistin dependence in A. baumannii involves an ensemble of mechanisms seen in resistance development and accompanied by complex cellular events related to insertional sequences (ISs)-triggered LOS-deficiency. To our knowledge, this is the first study demonstrating the involvement of ISAjo2 and ISAba13 IS elements in the modulation of the lipid A biosynthesis and associated development of dependence on colistin.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Acinetobacter/genética , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/patogenicidade , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Mutagênese Insercional/genética
8.
Biochem Pharmacol ; 184: 114400, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387481

RESUMO

Multidrug-resistant (MDR) Acinetobacter baumannii presents a critical challenge to human health worldwide and polymyxins are increasingly used as a last-line therapy. Due to the rapid emergence of resistance during polymyxin monotherapy, synergistic combinations (e.g. with rifampicin) are recommended to treat A. baumannii infections. However, most combination therapies are empirical, owing to a dearth of understanding on the mechanism of synergistic antibacterial killing. In the present study, we employed metabolomics to investigate the synergy mechanism of polymyxin B-rifampicin against A. baumannii AB5075, an MDR clinical isolate. The metabolomes of A. baumannii AB5075 were compared at 1 and 4 h following treatments with polymyxin B alone (0.75 mg/L, i.e. 3 × MIC), rifampicin alone (1 mg/L, i.e. 0.25 × MIC) and their combination. Polymyxin B monotherapy significantly perturbed glycerophospholipid and fatty acid metabolism at 1 h, reflecting its activity on bacterial outer membrane. Rifampicin monotherapy significantly perturbed glycerophospholipid, nucleotide and amino acid metabolism, which are related to the inhibition of RNA synthesis. The combination treatment significantly perturbed the metabolism of nucleotides, amino acids, fatty acids and glycerophospholipids at 1 and 4 h. Notably, the intermediate metabolite pools from pentose phosphate pathway were exclusively enhanced by the combination, while most metabolites from the nucleotide and amino acid biosynthesis pathways were significantly decreased. Overall, the synergistic activity of the combination was initially driven by polymyxin B which impacted pathways associated with outer membrane biogenesis; and subsequent effects were mainly attributed to rifampicin via the inhibition of RNA synthesis. This study is the first to reveal the synergistic killing mechanism of polymyxin-rifampicin combination against polymyxin-susceptible MDR A. baumannii at the network level. Our findings provide new mechanistic insights for optimizing this synergistic combination in patients.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/metabolismo , Antibacterianos/farmacologia , Polimixina B/farmacologia , Rifampina/farmacologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Glicerofosfolipídeos/metabolismo , Humanos , Metabolômica/métodos , Nucleotídeos/metabolismo , Fosfolipídeos/metabolismo
9.
Nat Microbiol ; 6(2): 157-161, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432151

RESUMO

We characterized two bacteriophages, ΦFG02 and ΦCO01, against clinical isolates of Acinetobacter baumannii and established that the bacterial capsule is the receptor for these phages. Phage-resistant mutants harboured loss-of-function mutations in genes responsible for capsule biosynthesis, resulting in capsule loss and disruption of phage adsorption. The phage-resistant strains were resensitized to human complement, beta-lactam antibiotics and alternative phages and exhibited diminished fitness in vivo. Using a mouse model of A. baumannii infection, we showed that phage therapy was effective.


Assuntos
Infecções por Acinetobacter/microbiologia , Infecções por Acinetobacter/terapia , Acinetobacter baumannii/virologia , Antibacterianos/farmacologia , Bacteriófagos/fisiologia , Terapia por Fagos , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Animais , Cápsulas Bacterianas/virologia , Proteínas do Sistema Complemento/farmacologia , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Feminino , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/farmacologia
10.
Eur J Med Chem ; 213: 113172, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33516984

RESUMO

The synthesis and biological evaluation of a series of phenanthroline-based visible-light-activated manganese(I) carbon-monoxide-releasing molecules (PhotoCORMs) against ESKAPE bacteria and bacterial biofilms is reported. Four carbonyl compounds of general formula fac-[Mn(N∧N)(CO)3(L)] have been synthesized and characterized. Despite being thermally stable in the absence of light, these PhotoCORMs readily release CO upon blue (435-450 nm) LED light irradiation as confirmed by spectrophotometric CO releasing experiments (Mb Assay). The antibacterial activity of the four PhotoCORMs has been investigated against a panel of ESKAPE bacteria. The compounds 1-3 were found to be effective antibacterials at low concentrations against multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumannii when photoactivated with blue-light. In addition, the PhotoCORMs 1-2 were found to inhibit the formation of Klebsiella pneumoniae and Acinetobacter baumannii bacterial biofilms at low concentrations (MIC = 4-8 µg/mL), turning out to be promising candidates to combat antimicrobial resistance. The antibacterial and biofilm inhibitory effect of the PhotoCORMs is plausibly due to the release of CO as well as the formation of phenanthroline photo-by-products as revealed by spectroscopy and microbiology experiments.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Desenvolvimento de Medicamentos , Klebsiella pneumoniae/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Monóxido de Carbono/química , Monóxido de Carbono/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Manganês/química , Manganês/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenantrolinas/química , Fenantrolinas/farmacologia , Processos Fotoquímicos , Relação Estrutura-Atividade
11.
J Ethnopharmacol ; 264: 113266, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32810621

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Bile traditionally was used in wound healing, having erodent, antioxidant and antimicrobial potential. Acinetobacter baumannii is a frequent etiological agent of wound infections, exhibiting high level of resistance to conventional antibiotics. AIM OF THE STUDY: To determine the effect of selected bile acid sodium salts and their 3-dehydro (i.e. 3-oxo) derivatives, as well as their combinations with commercial antibiotics against A. baumanniia, to confirm bile ethnopharmacological application in wound healing from aspect of microbiology. MATERIALS AND METHODS: The sensitivity of reference and multidrug resistant (MDR) A. baumannii strains to bile salts, their derivatives and conventional antibiotics were examined by a microtiter plate method. The interaction of bile salts/derivatives and antibiotics was examined by a checkerboard method and time kill curve method. The interaction of bile salts with ciprofloxacin in terms of micelles formation was examined by DOSY NMR technique. RESULTS: The bile salts sodium deoxycholate (Na-DCA) and sodium chenodeoxycholate (Na-CDCA), as well as their derivatives sodium 3-dehydro-deoxycholate (Na-3DH-DCA) and sodium 3-dehydro-chenodeoxycholate (Na-3DH-CDCA), potentiate antibiotic activity and resensitize A. baumannii. The bile salts and their derivatives enhance A. baumannii sensitivity to antibiotics, particularly those that should penetrate cell to exhibit activity. The sodium salts of bile acid derivatives, namely Na-3DH-DCA and Na-3DH-CDCA, showed synergy against both reference and MDR strain in combination with ciprofloxacin or gentamicin, while synergy with gentamicin was obtained in all combinations, regardless of bile salt type and bacterial strains. The synergy with Na-3DH-CDCA was further confirmed by the time-kill curve method, as bacterial number decreased after 12 h. NMR experiment revealed that this bile salt derivative and ciprofloxacin form co-aggregates when bile salts concentration was higher than critical micelle concentrations (CMC), which indicate the possibility that bile salts enhance ciprofloxacin cell penetration by membrane destabilization, contributing to the synergy. CONCLUSION: The synergistic interactions between bile salts or derivatives with ciprofloxacin and particularly gentamicin represent a promising strategy for the treatment of A. baumannii wound infections.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Anti-Infecciosos/administração & dosagem , Ácidos e Sais Biliares/administração & dosagem , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Acinetobacter baumannii/fisiologia , Ácidos e Sais Biliares/isolamento & purificação , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/fisiologia , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana/métodos
12.
Sci Rep ; 10(1): 21975, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319862

RESUMO

Acinetobacter baumannii (AB) is rising as a human pathogen of critical priority worldwide as it is the leading cause of chronic opportunistic infections in healthcare settings and the condition is ineradicable with antibiotic therapy. AB possesses the ability to form biofilm on abiotic as well as biotic surfaces which plays a major role in its pathogenesis and resistance in clinical settings. Hence, the demand for an alternative therapy to combat the biofilm-associated infections is increasing. The present study explored the antibiofilm potential of myrtenol, a bicyclic monoterpene present in various plants against reference and clinical strains of AB. Myrtenol (200 µg/mL) exhibited a strong antibiofilm activity without exerting any harmful effect on growth and metabolic viability of AB strains. Microscopic analyses confirmed the reduction in the biofilm thickness and surface coverage upon myrtenol treatment. Especially, myrtenol was found to be effective in disrupting the mature biofilms of tested AB strains. Furthermore, myrtenol inhibited the biofilm-associated virulence factors of AB strains such as extracellular polysaccharide, cell surface hydrophobicity, oxidant resistance, swarming and twitching motility. Transcriptional analysis unveiled the suppression of the biofilm-associated genes such as bfmR, csuA/B, bap, ompA, pgaA, pgaC, and katE by myrtenol. Notably, myrtenol improved the susceptibility of AB strains towards conventional antibiotics such as amikacin, ciprofloxacin, gentamicin and trimethoprim. Thus, the present study demonstrates the therapeutic potential of myrtenol against biofilm-associated infections of AB.


Assuntos
Acinetobacter baumannii/fisiologia , Acinetobacter baumannii/patogenicidade , Antibacterianos/farmacologia , Monoterpenos Bicíclicos/farmacologia , Biofilmes/efeitos dos fármacos , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/crescimento & desenvolvimento , Aderência Bacteriana/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Modelos Biológicos , Movimento , Oxidantes/toxicidade , Polissacarídeos/farmacologia , Virulência/efeitos dos fármacos
13.
Mem Inst Oswaldo Cruz ; 115: e200371, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33174904

RESUMO

BACKGROUND: Acinetobacter baumannii outbreaks have been associated with pandemic International Clones (ICs), but the virulence factors involved with their pathogenicity are sparsely understood. Pigment production has been linked with bacterial pathogenicity, however, this phenotype is rarely observed in A. baumannii. OBJECTIVES: This study aimed to characterise the reddish-brown pigment produced by A. baumannii strains, and to determine its biosynthetic pathway by genomic approaches. METHODS: Pigment characterisation and antimicrobial susceptibility were conducted by phenotypic tests. The clonal relationship was obtained by pulsed field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). The genome of an A. baumannii was obtained for characterisation of genes involved with pigment production. FINDINGS: The pyomelanin was the pigment produced by A. baumannii. Strains were extensively drug resistant and belonged to the IC-5/ST79. The pyomelanin biosynthetic pathway was determined and presented a particular architecture concerning the peripheral (tyrB, phhB and hpd) and central (hmgB, hmgC and hmgR) metabolic pathway genes. The identification of a distant HmgA homologue, probably without dioxygenase activity, could explain pyomelanin production. Virulence determinants involved with adherence (csuA/BABCDE and a T5bSS-carrying genomic island), and iron uptake (basABCDEFGHIJ, bauABCDEF and barAB) were characterised. MAIN CONCLUSION: There is a biosynthetic pathway compatible with the pyomelanin production observed in persistent A. baumannii IC-5 strains.


Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Vias Biossintéticas/genética , Melaninas , Acinetobacter baumannii/isolamento & purificação , Antibacterianos/farmacologia , Eletroforese em Gel de Campo Pulsado , Humanos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Pandemias , beta-Lactamases
14.
Artigo em Inglês | MEDLINE | ID: mdl-33206862

RESUMO

Acinetobacter baumannii is one of the most frequent nosocomial pathogen capable of acquiring resistance to different antimicrobials. The aim of this study was to investigate the activity of tetracycline, doxycycline and minocycline, the prevalence of tet(A) and tet(B) determinants, and the role of efflux pump in tetracycline resistance among the A. baumannii clinical isolates. Susceptibility of 98 A. baumannii isolates to tetracyclines was evaluated by disk diffusion method. The presence of active efflux pump was investigated by determination of the minimum inhibitory concentration (MIC) of tetracycline using the carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Polymerase chain reaction (PCR) was performed to investigate the presence of tet(A) and tet(B) determinants in tetracycline-resistant isolates. The rate of resistance to tetracycline, doxycycline and minocycline was 47.95%, 0%, and 30.61%, respectively. Among the 47 tetracycline-resistant isolates, 29.79% were originated from burned patients and showed MIC ranging from 128-256 µg/mL with both MIC 50 and MIC90 values of 256 µg/mL, while 70.21% were from ventilator-associated pneumonia (VAP) patients and had MIC values ranging from 32-1024 µg/mL, with MIC50 and MIC90 of 512 µg/mL and 1024 µg/mL, respectively. The tet(B) gene was found in 61.7% of tetracycline-resistant isolates, while none of the isolates carried the tet(A) gene. CCCP led to 2-128-fold reduction in tetracycline MIC of the tested isolates. The results showed that doxycycline and minocycline are promising agents for the treatment of A. baumannii infections. This study has also revealed the role of efflux activity in the resistance to tetracycline of A. baumannii isolates. The emergence of resistance to these agents is likely due to the spread of clones presenting with a higher prevalence of resistance determinants.


Assuntos
Acinetobacter baumannii , Antiporters/genética , Proteínas de Bactérias/genética , Resistência a Tetraciclina/genética , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Antibacterianos/farmacologia , Doxiciclina/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Minociclina/farmacologia
15.
BMC Infect Dis ; 20(1): 646, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873235

RESUMO

BACKGROUND: COVID-19 is known as a new viral infection. Viral-bacterial co-infections are one of the biggest medical concerns, resulting in increased mortality rates. To date, few studies have investigated bacterial superinfections in COVID-19 patients. Hence, we designed the current study on COVID-19 patients admitted to ICUs. METHODS: Nineteen patients admitted to our ICUs were enrolled in this study. To detect COVID-19, reverse transcription real-time polymerase chain reaction was performed. Endotracheal aspirate samples were also collected and cultured on different media to support the growth of the bacteria. After incubation, formed colonies on the media were identified using Gram staining and other biochemical tests. Antimicrobial susceptibility testing was carried out based on the CLSI recommendations. RESULTS: Of nineteen COVID-19 patients, 11 (58%) patients were male and 8 (42%) were female, with a mean age of ~ 67 years old. The average ICU length of stay was ~ 15 days and at the end of the study, 18 cases (95%) expired and only was 1 case (5%) discharged. In total, all patients were found positive for bacterial infections, including seventeen Acinetobacter baumannii (90%) and two Staphylococcus aureus (10%) strains. There was no difference in the bacteria species detected in any of the sampling points. Seventeen of 17 strains of Acinetobacter baumannii were resistant to the evaluated antibiotics. No metallo-beta-lactamases -producing Acinetobacter baumannii strain was found. One of the Staphylococcus aureus isolates was detected as methicillin-resistant Staphylococcus aureus and isolated from the patient who died, while another Staphylococcus aureus strain was susceptible to tested drugs and identified as methicillin-sensitive Staphylococcus aureus. CONCLUSIONS: Our findings emphasize the concern of superinfection in COVID-19 patients due to Acinetobacter baumannii and Staphylococcus aureus. Consequently, it is important to pay attention to bacterial co-infections in critical patients positive for COVID-19.


Assuntos
Infecções por Acinetobacter/complicações , Acinetobacter baumannii/isolamento & purificação , Betacoronavirus/fisiologia , Coinfecção/epidemiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Infecções Estafilocócicas/complicações , Staphylococcus aureus/isolamento & purificação , Infecções por Acinetobacter/epidemiologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Complicações do Diabetes/epidemiologia , Feminino , Cardiopatias/complicações , Humanos , Hipertensão/complicações , Unidades de Terapia Intensiva , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Sistema Respiratório/microbiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos
16.
Nat Commun ; 11(1): 4522, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908144

RESUMO

A unique, protective cell envelope contributes to the broad drug resistance of the nosocomial pathogen Acinetobacter baumannii. Here we use transposon insertion sequencing to identify A. baumannii mutants displaying altered susceptibility to a panel of diverse antibiotics. By examining mutants with antibiotic susceptibility profiles that parallel mutations in characterized genes, we infer the function of multiple uncharacterized envelope proteins, some of which have roles in cell division or cell elongation. Remarkably, mutations affecting a predicted cell wall hydrolase lead to alterations in lipooligosaccharide synthesis. In addition, the analysis of altered susceptibility signatures and antibiotic-induced morphology patterns allows us to predict drug synergies; for example, certain beta-lactams appear to work cooperatively due to their preferential targeting of specific cell wall assembly machineries. Our results indicate that the pathogen may be effectively inhibited by the combined targeting of multiple pathways critical for envelope growth.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Parede Celular/efeitos dos fármacos , Parede Celular/genética , Parede Celular/metabolismo , Infecção Hospitalar/microbiologia , Análise Mutacional de DNA , Elementos de DNA Transponíveis/genética , DNA Bacteriano/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Mutação
17.
Niger J Clin Pract ; 23(8): 1155-1162, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32788495

RESUMO

Objective: The blaOXA resistance genes and ISAba1 were examined in 70 samples from lower respiratory tract of hospitalized patients. Materials and Methods: Of the 67 isolates obtained, almost half (46.3%) of them were from endotracheal aspirate, and most were collected from the intensive care units of the reanimation (37.3%) and internal medicine (32.8%) units. Results: Three samples from the internal medicine intensive care unit had positive cultures. Of the multidrug resistant (MDR) samples, 70 isolates (>50%) were moderately sensitive, while fewer (10%) were resistant to tigecycline. In contrast, 100% were sensitive to colistin. All strains were found to be positive for blaOXA-23-like and blaOXA-51-like genes, whereas no blaOXA-40-like and blaOXA-58-like genes were detected. The ISAba1 positivity rate was 90.0%. Pattern 5 was mainly identified among the 22 different patterns. Of note, 50% of Pattern 5 was found in the patients of the internal medicine intensive care unit, and a third was associated with ventilator-associated pneumonia. Importantly, the internal medicine unit's equipment was found to be culture positive. Conclusion: Findings obtained from this study suggest that isolates can easily spread through the hospital via isolate cross-contamination caused by health personnel. These contaminating isolates may be able to maintain their presence within the hospital for a long time.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Acinetobacter baumannii/isolamento & purificação , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , beta-Lactamases/genética , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Bactérias/genética , Colistina/farmacologia , DNA Bacteriano/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Genes Bacterianos , Humanos , Unidades de Terapia Intensiva , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem Molecular , Reação em Cadeia da Polimerase Multiplex , Centros de Atenção Terciária
18.
PLoS One ; 15(8): e0238195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845920

RESUMO

Nosocomial infections caused by extensively drug-resistant (XDR) or Pan-Drug resistant (PDR) Acinetobacter (A.) baumannii have recently increased dramatically creating a medical challenge as therapeutic options became very limited. The aim of our study was to investigate the antibiotic-resistance profiles and evaluate the various combinations of ciprofloxacin (CIP) or levofloxacin (LEV) with antimicrobial agents and non-antimicrobial agents to combat antimicrobial resistance of XDR A. baumannii. A total of 100 (6.25%) A. baumannii clinical isolates were recovered from 1600 clinical specimens collected from hospitalized patients of two major university hospitals in Upper Egypt. Antimicrobial susceptibility tests were carried out according to CLSI guidelines. Antimicrobial susceptibility testing of the respective isolates showed a high percentage of bacterial resistance to 19 antimicrobial agents ranging from 76 to99%. However, a lower percentage of resistance was observed for only colistin (5%) and doxycycline (57%). The isolates were categorized as PDR (2; 2%), XDR (68; 68%), and multi-drug resistant (MDR) (30; 30%). Genotypic analysis using ERIC-PCR on 2 PDR and 32 selected XDR isolates showed that they were not clonal. Combinations of CIP or LEV with antibiotics (including, ampicillin, ceftriaxone, amikacin, or doxycycline) were tested on these A. baumannii non-clonal isolates using standard protocols where fractional inhibitory concentrations (-FICs) were calculated. Results of the respective combinations showed synergism in 23.5%, 17.65%, 32.35%, 17.65% and 26.47%, 8.28%, 14.71%, 26.47%, of the tested isolates, respectively. CIP or LEV combinations with either chlorpromazine (CPZ) 200 µg/ml, propranolol (PR) in two concentrations, 0.5 mg/ml and 1.0 mg/ml or diclofenac (DIC) 4 mg/ml were carried out and the MIC decrease factor (MDF) of each isolate was calculated and results showed synergism in 44%, 50%, 100%, 100% and 94%, 85%, 100%, 100%, of the tested isolates, respectively. In conclusion, combinations of CIP or LEV with CPZ, PR, or DIC showed synergism in most of the selected PDR and XDR A. baumannii clinical isolates. However, these combinations have to be re-evaluated in vivo using appropriate animal models infected by XDR- or PDR- A. baumannii.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Clorpromazina/farmacologia , Diclofenaco/farmacologia , Fluoroquinolonas/farmacologia , Propranolol/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/genética , Acinetobacter baumannii/isolamento & purificação , Ciprofloxacino/farmacologia , Infecção Hospitalar/microbiologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Egito , Humanos , Levofloxacino/farmacologia
19.
BMC Infect Dis ; 20(1): 597, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32787942

RESUMO

BACKGROUND: Multidrug resistant (MDR) and extensively drug resistant (XDR) Acinetobacter baumannii presents challenges for clinical treatment and causes high mortality in children. We aimed to assess the risk factors and overall mortality for MDR/XDR Acinetobacter baumannii infected pediatric patients. METHODS: This retrospective study included 102 pediatric patients who developed MDR/XDR Acinetobacter baumannii infection in the pediatric intensive care unit (PICU) of Shanghai Children's Hospital in China from December 2014 to May 2018. Acinetobacter baumannii clinical isolates were recovered from different specimens including blood, sputum, bronchoalveolar lavage fluid, cerebrospinal fluid, ascites, hydrothorax, and urine. Antibiotic susceptibility test was determined according to the Clinical and Laboratory Standards Institute interpretive criteria. Clinical and biological data were obtained from the patients' medical records. RESULTS: 102 patients with Acinetobacter baumannii infection were enrolled. The median age was 36 (9.6, 98.8) months, and there were 63 male in the case group. The overall mortality rate was 29.4%, while the Acinetobacter baumannii-associated mortality rate was 16.7% (17/102, 12 bloodstream infections, 4 meningitis and 1 intra-abdominal infection). Bloodstream infections occurred in 28 patients (27.5%), and 10 patients (9.8%) among them had central line-associated bloodstream infections (6 central venous catheters, 2 PICCs, 1 venous infusion port and 1 arterial catheter). Cerebrospinal fluid (CSF) cultures were positive in 4(3.9%) patients. 14(13.7%) patients got positive cultures in ascites and hydrothorax. Lower respiratory isolates (56/102) accounted for 54.9% of all patients. Non-survival patients appeared to have a lower NK cell activity (6.2% ± 3.61% vs. 9.15% ± 6.21%, P = 0.029), higher CD4+ T cell ratio (39.67% ± 12.18% vs. 32.66% ± 11.44%, P = 0.039),and a higher serum level of interlukin-8 (IL-8, 15.25 (1.62, 47.22)pg/mL vs. 0.1 (0.1, 22.99)pg/mL, P = 0.01) when Acinetobacter baumannii infection developed. Multivariate logistic analysis indicated that high serum level of Cr (RR, 0.934, 95%CI, 0.890-0.981; P = 0.007) and high BUN/ALB level (RR, 107.893, 95%CI, 1.425-870.574; p = 0.005) were associated with high risk of mortality in MDR/XDR Acinetobacter baumannii infected patients. CONCLUSION: MDR/XDR Acinetobacter baumannii infection is a serious concern in pediatric patients with high mortality. Bloodstream and central nervous system infection accounted for high risk of death. Acute kidney injury is associated with high risk of mortality.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/mortalidade , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/mortalidade , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Unidades de Terapia Intensiva Pediátrica , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/isolamento & purificação , Lesão Renal Aguda/mortalidade , Bacteriemia/mortalidade , Infecções do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , China , Infecção Hospitalar/microbiologia , Feminino , Hospitais , Humanos , Lactente , Masculino , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
20.
PLoS One ; 15(8): e0235723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797045

RESUMO

Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.


Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Extratos Vegetais/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Anacardiaceae/química , Antibacterianos/isolamento & purificação , Produtos Biológicos/isolamento & purificação , Fracionamento Químico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Humanos , Extratos Vegetais/isolamento & purificação
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