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1.
Planta Med ; 85(16): 1253-1262, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31597166

RESUMO

The development of multiple antibiotic-resistant bacteria has vastly depleted our repertoire of effective antibiotic chemotherapies. The development of multi-ß-lactam-resistant strains are particularly concerning due to our previous reliance on this class of antibiotics because of their initial efficacy and broad-spectrum activity. With increases in extended-spectrum ß-lactam-resistance and an expanded resistance to other classes of antibiotics, there is an urgent need for the development of effective new antibiotic therapies. Terminalia ferdinandiana is an endemic Australian plant known for its high antioxidant and tannin contents. T. ferdinandiana fruit and leaf extracts have strong antibacterial activity against a wide variety of bacterial pathogens. However, T. ferdinandiana extracts have not been tested against ESBL and MRSA antibiotic-resistant pathogens. An objective of this study was to screen T. ferdinandiana fruit and leaf extracts for bacterial growth inhibitory activity by disc diffusion assay against ß-lactam-sensitive and -resistant E. coli strains and against methicillin-sensitive and -resistant S. aureus. The minimum inhibitory concentration (MIC) was quantified by liquid dilution techniques. The fruit methanolic extract, as well as the methanolic, aqueous, and ethyl acetate leaf extracts strongly inhibited the growth of the MRSA, with MICs as low as 223 µg/mL. In contrast, the extracts were ineffective inhibitors of ESBL growth. Metabolomic fingerprint analysis identified a diversity and relative abundance of tannins, flavonoids, and terpenoids, several of which have been reported to inhibit MRSA growth in isolation. All extracts were nontoxic in the Artemia nauplii and HDF toxicity assays, further indicating their potential for medicinal use.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Artemia/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Terminalia/química , Animais , Frutas/química , Metanol , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Folhas de Planta/química
2.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383747

RESUMO

Postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) infection can quickly develop into severe, necrotizing pneumonia, causing over 50% mortality despite antibiotic treatments. In this study, we investigated the efficacy of antibiotic therapies and the impact of S. aureus alpha-toxin in a model of lethal influenza virus and MRSA coinfection. We demonstrate that antibiotics primarily attenuate alpha-toxin-induced acute lethality, even though both alpha-toxin-dependent and -independent mechanisms significantly contribute to animal mortality after coinfection. Furthermore, we found that the protein synthesis-suppressing antibiotic linezolid has an advantageous therapeutic effect on alpha-toxin-induced lung damage, as measured by protein leak and lactate dehydrogenase (LDH) activity. Importantly, using a Panton-Valentine leucocidin (PVL)-negative MRSA isolate from patient sputum, we show that linezolid therapy significantly improves animal survival from postinfluenza MRSA pneumonia compared with vancomycin treatment. Rather than improved viral or bacterial control, this advantageous therapeutic effect is associated with a significantly attenuated proinflammatory cytokine response and acute lung damage in linezolid-treated mice. Together, our findings not only establish a critical role of alpha-toxin in the extreme mortality of secondary MRSA pneumonia after influenza but also provide support for the possibility that linezolid could be a more effective treatment than vancomycin to improve disease outcomes.


Assuntos
Antibacterianos/farmacologia , Toxinas Bacterianas/antagonistas & inibidores , Proteínas Hemolisinas/antagonistas & inibidores , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções por Orthomyxoviridae/complicações , Pneumonia Estafilocócica/tratamento farmacológico , Animais , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Feminino , Expressão Gênica , Gentamicinas/farmacologia , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , L-Lactato Desidrogenase/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Plasmídeos/química , Plasmídeos/metabolismo , Pneumonia Estafilocócica/complicações , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Análise de Sobrevida , Vancomicina/farmacologia
3.
APMIS ; 127(11): 717-726, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31407405

RESUMO

This study aims to determine the prevalence of Staphylococcus aureus colonizing patients and ICU environment of a teaching hospital, the virulence and antimicrobial susceptibility profile of the isolates, and to evaluate the genetic relationship among them. A total of 536 swabs (134 of patients and 402 of ICU environment) were collected and analyzed to detect S. aureus. The antimicrobial susceptibility of the isolates was determined by disk diffusion test, and the detection of the mecA and virulence factors genes was performed by PCR, in addition to SCCmec typing. The genetic similarity of the isolates was determined by PFGE. Staphylococcus aureus was isolated in 12.7% of the swabs. The prevalence of colonization was 13.4% in patients and 12.4% in the environmental samples. The multidrug resistance was determined in 82.4% of the isolates. The prevalence of methicillin-resistant S. aureus was 20.6%, with 50.0% classified as SCCmec IV. The intermediate resistance to vancomycin was detected in 5.9% and 4.4% of the isolates obtained from patients and environment, respectively. Identical isolates obtained from different patients and sources were grouped into several clusters. The results showed dissemination of multidrug-resistant strains between patients and fomites and the persistence of MRSA and VISA isolates in the ICU environment.


Assuntos
Antibacterianos/farmacologia , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidade , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana , Feminino , Variação Genética , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Filogenia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Vancomicina/farmacologia , Virulência , Fatores de Virulência/genética
4.
Molecules ; 24(16)2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31426567

RESUMO

A series of twenty-six methoxylated and methylated N-aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of N-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S. aureus as well as against Mycobacterium tuberculosis and M. kansasii. In addition, the inhibitory profile of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of N-(3,5-dimethylphenyl)-, N-(3-fluoro-5-methoxy-phenyl)- and N-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration >30 µM. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log k), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure-activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.


Assuntos
Anilidas/farmacologia , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mycobacterium kansasii/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Naftóis/farmacologia , Ampicilina/farmacologia , Anilidas/síntese química , Anilidas/química , Antibacterianos/síntese química , Antibacterianos/química , Cloroplastos/efeitos dos fármacos , Cloroplastos/fisiologia , Transporte de Elétrons/efeitos dos fármacos , Humanos , Isoniazida/farmacologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Metilação , Testes de Sensibilidade Microbiana , Mycobacterium kansasii/crescimento & desenvolvimento , Mycobacterium tuberculosis/crescimento & desenvolvimento , Naftóis/síntese química , Naftóis/química , Fotossíntese/efeitos dos fármacos , Análise de Componente Principal , Spinacia oleracea/química , Spinacia oleracea/efeitos dos fármacos , Spinacia oleracea/metabolismo , Relação Estrutura-Atividade , Células THP-1
5.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426277

RESUMO

Multidrug resistance (MDR) causes challenging tasks in medicine. Human cancer cells, as well as microorganisms, can acquire multiresistance due to the up-regulation of efflux pumps (ABC transporters) and are difficult to treat. Here, we evaluated the effects of chlorophyll, the most abundant pigment on the globe, and its derivative, pheophytin, on cancer cells and methicillin-resistant Staphylococcus aureus (MRSA). We found that both substances have significant reversal effects on multidrug-resistant CEM/ADR5000 cells (RRpheophytin = 3.13, combination index (CI)pheophytin = 0.438; RRchlorophyll = 2.72, CIchlorophyll < 0.407), but not on drug-sensitive CCRF-CEM cells when used in combination with doxorubicin. This indicates that the porphyrins could interact with efflux pumps. Strong synergism was also observed in antimicrobial tests against MRSA when combining ethidium bromide with chlorophyll (FICI = 0.08). As there is a strong need for new drugs in order to reliably treat MDR cells, our research provides potential candidates for further investigation.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Clorofila/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etídio/farmacologia , Feofitinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana
6.
PLoS Comput Biol ; 15(7): e1007087, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31295255

RESUMO

Persistent bacteremia caused by Staphylococcus aureus (SA), especially methicillin-resistant SA (MRSA), is a significant cause of morbidity and mortality. Despite susceptibility phenotypes in vitro, persistent MRSA strains fail to clear with appropriate anti-MRSA therapy during bacteremia in vivo. Thus, identifying the factors that cause such MRSA persistence is of direct and urgent clinical relevance. To address the dynamics of MRSA persistence in the face of host immunity and typical antibiotic regimens, we developed a mathematical model based on the overarching assumption that phenotypic heterogeneity is a hallmark of MRSA persistence. First, we applied an ensemble modeling approach and obtained parameter sets that satisfied the condition of a minimum inoculum dose to establish infection. Second, by simulating with the selected parameter sets under vancomycin therapy which follows clinical practices, we distinguished the models resulting in resolving or persistent bacteremia, based on the total SA exceeding a detection limit after five days of treatment. Third, to find key determinants that discriminate resolving and persistent bacteremia, we applied a machine learning approach and found that the immune clearance rate of persister cells is a key feature. But, fourth, when relapsing bacteremia was considered, the growth rate of persister cells was also found to be a key feature. Finally, we explored pharmacological strategies for persistent and relapsing bacteremia and found that a persister killer, but not a persister formation inhibitor, could provide for an effective cure the persistent bacteremia. Thus, to develop better clinical solutions for MRSA persistence and relapse, our modeling results indicate that we need to better understand the pathogen-host interactions of persister MRSAs in vivo.


Assuntos
Bacteriemia/microbiologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Infecções Estafilocócicas/microbiologia , Antibacterianos/farmacologia , Feminino , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Modelos Teóricos
7.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340560

RESUMO

BACKGROUND: Due to current antibiotic resistance worldwide, there is an urgent need to find new alternative antibacterial approaches capable of dealing with multidrug-resistant pathogens. Most recent studies have demonstrated the antibacterial activity and non-cytotoxicity of carbon nanomaterials such as graphene oxide (GO) and carbon nanofibers (CNFs). On the other hand, light-emitting diodes (LEDs) have shown great potential in a wide range of biomedical applications. METHODS: We investigated a nanotechnological strategy consisting of GO or CNFs combined with light-emitting diod (LED) irradiation as novel nanoweapons against two clinically relevant Gram-positive multidrug-resistant pathogens: methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). The cytotoxicity of GO and CNFs was studied in the presence of human keratinocyte HaCaT cells. RESULTS: GO or CNFs exhibited no cytotoxicity and high antibacterial activity in direct contact with MRSE and MRSA cells. Furthermore, when GO or CNFs were illuminated with LED light, the MRSE and MRSA cells lost viability. The rate of decrease in colony forming units from 0 to 3 h, measured per mL, increased to 98.5 ± 1.6% and 95.8 ± 1.4% for GO and 99.5 ± 0.6% and 99.7 ± 0.2% for CNFs. CONCLUSIONS: This combined antimicrobial approach opens up many biomedical research opportunities and provides an enhanced strategy for the prevention and treatment of Gram-positive multidrug-resistant infections.


Assuntos
Antibacterianos/farmacologia , Grafite/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos da radiação , Nanoestruturas/química , Nanotubos de Carbono/química , Staphylococcus epidermidis/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Técnicas de Cocultura , Relação Dose-Resposta à Radiação , Humanos , Queratinócitos/citologia , Queratinócitos/fisiologia , Queratinócitos/efeitos da radiação , Luz , Resistência a Meticilina/efeitos da radiação , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos da radiação , Nanoestruturas/ultraestrutura , Nanotubos de Carbono/ultraestrutura , Fototerapia/métodos , Staphylococcus epidermidis/crescimento & desenvolvimento
8.
BMC Complement Altern Med ; 19(1): 185, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345195

RESUMO

BACKGROUND: Honey has been increasingly recognized as a potential therapeutic agent for treatment of wound infections. There is an urgent need for assessment and evaluation of the antibacterial properties against wound pathogens of honeys that have not yet been tested. METHODS: Ten Saudi honeys collected from different geographical locations were screened initially for their antibacterial potential against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) by the agar well diffusion method. Manuka honey (UMF-12) was used for comparison. Of the tested honeys, the honey that exhibited the greatest antibacterial activity in the agar well diffusion assay was further evaluated for its minimum inhibitory concentration (MIC) against ten MRSA clinical isolates and three American Type Culture Collection (ATCC) reference strains by the microbroth dilution method. RESULTS: Locally produced honeys exhibited variable antibacterial activity against the tested isolates in the agar well diffusion assay. They were unable to exhibit antibacterial activity against MSSA and MRSA at 25% dilutions (w/v) in catalase solution. However, Sumra and Talha honeys showed a zone of inhibition at 50% dilutions (w/v) in catalase solution. This finding means that both honeys possess weak non-peroxide-based antibacterial activity. Moreover, Sumra honey showed a larger inhibition zone at 50 and 25% dilutions (w/v) in distilled water than Manuka honey against both MSSA and MRSA. This result demonstrates that Sumra honey has more hydrogen peroxide-related antibacterial activity or total antibacterial activity than Manuka honey. In addition, MIC results obtained through a microbroth dilution assay showed that Sumra honey inhibited the growth of all MRSA clinical isolates (n = 10) and reference strains [MRSA (ATCC 43300) and MSSA (ATCC 29213)] at lower concentrations (12.0% v/v) than those required for Manuka honey-mediated inhibition (14.0% v/v). This result means that Sumra honey has more peroxide or synergistic antibacterial activity than Manuka honey. An equivalent MIC (15.0% v/v) was observed for E. coli (ATCC 25922) between Manuka honey and Sumra honey. CONCLUSIONS: Sumra honey may be used as an alternative therapeutic agent for infected wounds and burns, where additional hydrogen peroxide-related antibacterial activity is needed. In the future, the physiochemical characteristics of Sumra honey may be evaluated and standardized.


Assuntos
Antibacterianos/farmacologia , Mel/análise , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/análise , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Humanos , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Arábia Saudita , Staphylococcus aureus/efeitos dos fármacos
9.
Mater Sci Eng C Mater Biol Appl ; 103: 109778, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349506

RESUMO

Herein, we electrospun ultrathin core-shell fibers based on polycaprolactone (PCL), polyethylene glycol (PEG), gelatin and osteogenic growth peptide (OGP), and evaluated their potential to upregulate human osteoblast cells (hFOB) and to reduce Gram-positive and Gram-negative bacteria. We also evaluated the fiber morphology, chemical structure and peptide delivery efficacy. The employment of core-shell fibers compared to fibers without a core-shell showed improved mechanical strength, comparable to the strength of pure PCL, as well as improved hydrophilicity and wettability. The careful selection of polymer combination and core-shell strategy promoted a controlled and sustained release of OGP. Moreover, increased calcium deposition (CD) (1.3-fold) and alkaline phosphate (ALP) activity was observed when hFOBs were cultivated onto core-shell fibers loaded with OGP after 21 days of culture. Our developed scaffolds were also able to reduce the amount of Pseudomonas aeruginosa (ATCC 25668) bacteria by a factor of two compared to raw PCL without the use of any antibiotics. All of these results demonstrate a promising potential of the developed core-shell electrospun scaffolds based on PCL:PEG:Gelatin:OGP for numerous bone tissue applications.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Histonas , Peptídeos e Proteínas de Sinalização Intercelular , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Osteoblastos/metabolismo , Pseudomonas aeruginosa/crescimento & desenvolvimento , Engenharia Tecidual , Tecidos Suporte/química , Linhagem Celular , Histonas/química , Histonas/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia
10.
ACS Appl Mater Interfaces ; 11(31): 27574-27587, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31310503

RESUMO

A novel biscarbazol triphenylamine end-capped dendrimeric zinc(II) porphyrin (DP 5) was synthesized by click chemistry. This compound is a cruciform dendrimer that bears a nucleus of zinc(II) tetrapyrrolic macrocycle substituted at the meso positions by four identical substituents. These are formed by a tetrafluorophenyl group that possesses a triazole unit in the para position. This nitrogenous heterocyclic is connected to a 4,4'-di(N-carbazolyl)triphenylamine group by means of a phenylenevinylene bridge, which allows the conjugation between the nucleus and this external electropolymerizable carbazoyl group. In this structure, dendrimeric arms act as light-harvesting antennas, increasing the absorption of blue light, and as electroactive moieties. The electrochemical oxidation of the carbazole groups contained in the terminal arms of the DP 5 was used to obtain novel, stable, and reproducible fully π-conjugated photoactive polymeric films (FDP 5). First, the spectroscopic characteristics and photodynamic properties of DP 5 were compared with its constitutional components derived of porphyrin P 6 and carbazole D 7 moieties in solution. The fluorescence emissions of the dendrimeric units in DP 5 were more strongly quenched by the tetrapyrrolic macrocycle, indicating photoinduced energy transfer. In addition, FDP 5 film showed the Soret and Q absorption bands and red fluorescence emission of the corresponding zinc(II) porphyrin. Also, FDP 5 film was highly stable to photobleaching, and it was able to produce singlet molecular oxygen in both N,N-dimethylformamide (DMF) and water. Therefore, the porphyrin units embedded in the polymeric matrix of FDP 5 film mainly retain the photochemical properties. Photodynamic inactivation mediated by FDP 5 film was investigated in Staphylococcus aureus and Escherichia coli. When a cell suspension was deposited on the surface, complete eradication of S. aureus and a 99% reduction in E. coli survival were found after 15 and 30 min of irradiation, respectively. Also, FDP 5 film was highly effective to eliminate individual bacteria attached to the surface. In addition, photodynamic inactivation (PDI) sensitized by FDP 5 film produced >99.99% bacterial killing in biofilms formed on the surface after 60 min irradiation. The results indicate that FDP 5 film represents an interesting and versatile photodynamic active material to eradicate bacteria as planktonic cells, individual attached microbes, or biofilms.


Assuntos
Anti-Infecciosos/química , Carbazóis/química , Dendrímeros/química , Escherichia coli/crescimento & desenvolvimento , Membranas Artificiais , Metaloporfirinas/química , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento
11.
BMC Complement Altern Med ; 19(1): 150, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242939

RESUMO

BACKGROUND: Traditional medicine remedies are commonly used for treatment of diverse ailments including bacterial infections. The activity against resistant bacteria and safety of some remedies sold as anti-infective treatments in market places in Buea, Southwest Cameroon were investigated as potential alternative treatment to counter increasing antibiotic resistance. METHODS: Ten remedies were purchased, their components documented and microbial load estimated. Methanol extracts of the remedies were tested for antibacterial activity by disc diffusion and microdilution. Cytotoxicity was evaluated on monkey kidney epithelial cells (LLC-MK2) while acute oral toxicity was done in BALB/c mice for the bactericidal extract. Extracts were further analysed using phytochemical tests. RESULTS: All the remedies had microbial loads above the acceptable limit of 105 CFU/g. The highest activity was produced by extracts of four remedies (TP 1, 2, 4, 6a, 6b) against all clinical isolates among which three were active against four control strains. Zones of inhibition ranged from 8 to 27 mm. Two of the four extracts produced zones ≥20 mm against multidrug resistant clinical isolates of Citrobacter freundii and Escherichia coli but were less active compared to Gentamycin positive control (P < 0.0001-0.0014). The most active extracts also recorded minimum inhibitory concentrations of 1 to 4 mg/mL. One of them (TP2) was bactericidal against a clinical isolate of methicillin-resistant Staphylococcus aureus with a minimum bactericidal concentration of 8 mg/mL. Extracts of six remedies did not show cytotoxicity and no mortality or adverse effect was recorded in the acute oral toxicity test. Phytochemical screening showed the most active extracts contained relatively high amounts of alkaloids and flavonoids. CONCLUSION: Only four of the eight remedies tested showed activity against multidrug resistant bacteria suggesting some of these remedies may not be effective against bacterial infections. Production and handling methods should be improved and the product quality controlled to ensure biosecurity. The remedies which were both active and non-toxic should be further investigated including in vivo experiments to assess their efficacy.


Assuntos
Antibacterianos/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Camarões , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Feminino , Humanos , Medicina Tradicional , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Plantas Medicinais/microbiologia
12.
Nat Microbiol ; 4(10): 1680-1691, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31235959

RESUMO

Antibiotic resistance in bacterial pathogens threatens the future of modern medicine. One such resistant pathogen is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to nearly all ß-lactam antibiotics, limiting treatment options. Here, we show that a significant proportion of MRSA isolates from different lineages, including the epidemic USA300 lineage, are susceptible to penicillins when used in combination with ß-lactamase inhibitors such as clavulanic acid. Susceptibility is mediated by a combination of two different mutations in the mecA promoter region that lowers mecA-encoded penicillin-binding protein 2a (PBP2a) expression, and in the majority of isolates by either one of two substitutions in PBP2a (E246G or M122I) that increase the affinity of PBP2a for penicillin in the presence of clavulanic acid. Treatment of S. aureus infections in wax moth and mouse models shows that penicillin/ß-lactamase inhibitor susceptibility can be exploited as an effective therapeutic choice for 'susceptible' MRSA infection. Finally, we show that isolates with the PBP2a E246G substitution have a growth advantage in the presence of penicillin but the absence of clavulanic acid, which suggests that penicillin/ß-lactamase susceptibility is an example of collateral sensitivity (resistance to one antibiotic increases sensitivity to another). Our findings suggest that widely available and currently disregarded antibiotics could be effective in a significant proportion of MRSA infections.


Assuntos
Proteínas de Bactérias/genética , Ácido Clavulânico/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Proteínas de Ligação às Penicilinas/genética , Penicilinas/farmacologia , Inibidores de beta-Lactamases/farmacologia , Substituição de Aminoácidos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Proteínas de Bactérias/metabolismo , Ácido Clavulânico/uso terapêutico , Quimioterapia Combinada , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Camundongos , Testes de Sensibilidade Microbiana , Mariposas , Mutação , Proteínas de Ligação às Penicilinas/metabolismo , Penicilinas/metabolismo , Penicilinas/uso terapêutico , Regiões Promotoras Genéticas , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Resistência beta-Lactâmica/efeitos dos fármacos , Inibidores de beta-Lactamases/uso terapêutico
13.
Pak J Pharm Sci ; 32(2): 631-636, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31081776

RESUMO

Camellia sinensis is being used for decades for its therapeutic efficacies against physiological problems and microbial infections. This study was undertaken to investigate the antibacterial and antifungal potential of aqueous extract of Camellia sinensis. Antibacterial activity was determined by disc and well diffusion assay. MIC and MBC were calculated by broth dilution method. Miles and Misra technique was used to find out colony forming unit per/ml. All the test organisms revealed a diverse range of vulnerability against aqueous extract. Among Gram positive, MRSA showed to be the most sensitive with least MIC and MBC while among Gram-negative Pseudomonas aeruginosa exhibited the highest sensitivity. In Miles and Misra, a progressive decline in log of CFU/ml was observed. In time-kill assay, a decline was noted in the viable count of S.aureus after exposure to 18% aqueous extract of Camellia sinensis. In the present study aqueous extract of Camellia sinensis found to be effective against Gram positive, Gram negative and fungi. The most important finding of this study is its aqueous extract inhibitory effect against drug-resistant microorganisms e.g. MRSA and P. aeruginosa and Candida albicans.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Camellia sinensis/química , Extratos Vegetais/farmacologia , Antibacterianos/química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Pseudomonas aeruginosa/efeitos dos fármacos
14.
J Med Microbiol ; 68(6): 961-972, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31107198

RESUMO

PURPOSE: Antibiotic-loaded polymethylmethacrylate-based bone cement has been implemented in orthopaedics to cope with implant-related infections associated with the formation of bacterial biofilms. In the context of emerging bacterial resistance to current antibiotics, we examined the efficacy of short antimicrobial peptide-loaded bone cement in inhibiting bacterial adhesion and consequent biofilm formation on its surface. METHODOLOGY: The ability of α-helical antimicrobial peptides composed of 12 amino acid residues to prevent bacterial biofilm [methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli] formation on the surface of model implants made from polymethylmethacrylate-based bone cement was evaluated by colony-forming unit (c.f.u.) counting of bacteria released by sonication from the biofilms formed on their surfaces. The biofilms on model implant surfaces were also visualized by light microscopy after staining with tetrazolium dye (MTT) and by scanning electron microscopy. RESULTS: When incorporated in the implants, these peptides caused a mean reduction in the number of bacterial cells attached to implants' surfaces (by five orders of magnitude), and 88 % of these implants showed no bacterial adhesion after being exposed to growth media containing various bacteria. CONCLUSION: The results showed that the antibiofilm activity of these peptides was comparable to that of the antibiotics, but the peptides exhibited broader specificity than the antibiotics. Given the rapid development of antibiotic resistance, antimicrobial peptides show promise as a substitute for antibiotics for loading into bone cements.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Cimentos para Ossos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Peptídeos/síntese química , Polimetil Metacrilato , Próteses e Implantes/microbiologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus epidermidis/crescimento & desenvolvimento
15.
Surg Infect (Larchmt) ; 20(6): 472-479, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31038392

RESUMO

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is an urgent medical problem in osteomyelitis. The YycFG two-component regulatory system (TCS) allows bacteria to adapt rapidly to physical, chemical, and biological stresses. The recombinant plasmid shuttle vector was used to overexpress an antisense RNA (asRNA) to inhibit target gene expression by sequence-specific double-stranded RNA complex degradation. In the current study, antisense yycG RNA (ASyycG)-overexpression MRSA clinical isolates were constructed. Methods: Bacterial growth was monitored, and biofilm biomass was determined by crystal violet microtiter assay. Quantitative reverse transcription polymerase chain reaction analysis was used to identify expression of yycF/G/H and icaA/D in MRSA and ASyycG strains. The expression of YycG protein was quantified by Western blot assays. The antibiotic resistance of ASyycG strains was compared with that of the MRSA strains. Results: The ASyycG strains showed a decrease in growth rate compared with the MRSA strains. Of note, overexpression of ASyycG led to a reduction in biofilm formation and adhesion force. ASyycG strains had decreased expressions of the yycF/G/H and icaA/D. Furthermore, Western blot data showed that expression of the YycG protein decreased by 40% in ASyycG strains compared with MRSA strains. In addition, the effect of yycG asRNA improved the susceptibility of ASyycG strains to cefoxitin. Conclusions: The ASyycG strains inhibited biofilm organization and increased antibiotic sensitivity, which may be attributed to altered intracellular polysaccharide construction.


Assuntos
Biofilmes/crescimento & desenvolvimento , Histidina Quinase/antagonistas & inibidores , Staphylococcus aureus Resistente à Meticilina/enzimologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , RNA Antissenso/metabolismo , Antibacterianos/farmacologia , Cefoxitina/farmacologia , Perfilação da Expressão Gênica , Histidina Quinase/genética , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , RNA Antissenso/genética
16.
Medicine (Baltimore) ; 98(18): e15499, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045837

RESUMO

Given the emergence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) as a global health threat, understanding the risk factors for MRSA infection in the community may be a reasonable strategy to prevent it. We investigated the associations between serum homocysteine levels and prevalence of nasal colonization with S aureus and MRSA among United States adults. We conducted a cross-sectional analysis of a nationally representative sample of 7832 adults (20 years or older). The main outcome variables were nasal colonization with S aureus and MRSA. Percentages of colonization with S aureus and MRSA were calculated by the quartiles of serum homocysteine. A total of 7832 of 2051 subjects (26.2%) were culture positive for S aureus, 98 (4.8%) of whom had nasal colonization with MRSA. In comparison with subjects having the lowest serum homocysteine, the odds of nasal colonization with MRSA were significantly higher in those with the highest homocysteine (odds ratio, 3.09; 95% confidence interval, 1.11-8.61) in multivariate analysis, adjusted for all confounding variables. By contrast, homocysteine elevation was not significantly associated with S aureus colonization. Nasal colonization with MRSA in the general community was significantly associated with increases in serum homocysteine levels.


Assuntos
Homocisteína/sangue , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Cavidade Nasal/microbiologia , Infecções Estafilocócicas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Colônia Microbiana , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Razão de Chances , Prevalência , Fatores de Risco , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Estados Unidos/epidemiologia , Adulto Jovem
17.
PLoS One ; 14(5): e0217504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31136634

RESUMO

The recent emergence of antibiotic-resistant bacteria requires the development of new antibiotics or new agents capable of enhancing antibiotic activity. This study evaluated the antibacterial activity of lysozyme-chitosan oligosaccharide conjugates (LYZOX) against Pseudomonas aeruginosa, Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which should resolve the problem of antibiotic-resistant bacteria. Bactericidal tests showed that LYZOX killed 50% more P. aeruginosa (NBRC 13275), A. baumannii and MRSA than the control treatment after 60 min. In addition, LYZOX was shown to inhibit the growth of P. aeruginosa (NBRC 13275 and PAO1), A. baumannii and MRSA better than its components. To elucidate the antibacterial mechanism of LYZOX, we performed cell membrane integrity assays, N-phenyl-1-naphthylamine assays, 2-nitrophenyl ß-D-galactopyranoside assays and confocal laser scanning microscopy. These results showed that LYZOX affected bacterial cell walls and increased the permeability of the outer membrane and the plasma membrane. Furthermore, each type of bacteria treated with LYZOX was observed by electron microscopy. Electron micrographs revealed that these bacteria had the morphological features of both lysozyme-treated and chitosan oligosaccharide-treated bacteria and that LYZOX destroyed bacterial cell walls, which caused the release of intracellular contents from cells. An acquired drug resistance test revealed that these bacteria were not able to acquire resistance to LYZOX. The hemolytic toxicity test demonstrated the low hemolytic activity of LYZOX. In conclusion, LYZOX exhibited antibacterial activity and low drug resistance in the presence of P. aeruginosa, A. baumannii and MRSA and showed low hemolytic toxicity. LYZOX affected bacterial membranes, leading to membrane disruption and the release of intracellular contents and consequent bacterial cell death. LYZOX may serve as a novel candidate drug that could be used for the control of refractory infections.


Assuntos
Acinetobacter baumannii/crescimento & desenvolvimento , Antibacterianos , Quitosana , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Muramidase , Oligossacarídeos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Antibacterianos/química , Antibacterianos/farmacologia , Quitosana/química , Quitosana/farmacologia , Muramidase/química , Muramidase/farmacologia , Oligossacarídeos/química , Oligossacarídeos/farmacologia
18.
Microb Drug Resist ; 25(5): 668-676, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31099708

RESUMO

Characteristics of Staphylococcus aureus infections include biofilm formation, leading to the spread of bacteria to the bloodstream causing sepsis and metastatic infections. In particular, in methicillin-resistant S. aureus (MRSA) infections, biofilm formation critically hampers treatment and causes poor prognosis. We explored the biofilm formation of MRSA in the presence or absence of plasma and compared morphological characteristics, accumulation of antibiotics, and resistance to bactericidal activity, using continuous optimizing confocal reflection microscopy. Addition of plasma significantly increased biofilm formation, which is characterized by an uneven surface and aggregation of bacteria (hereafter plasma biofilm). The flow-cell system, which enabled a continuous supply of plasma, accelerated biofilm formation in both the tested strains of MRSA (BAA1556 and N315). Accumulation of green fluorescence-labeled vancomycin was observed within 5 minutes in the plasma-free biofilm, but not in the plasma biofilm. Delay of accumulation was also observed for daptomycin in plasma biofilm. Plasma biofilm bacteria were more resistant to anti-MRSA antibiotics than plasma-free biofilm bacteria. These data demonstrate that the plasma biofilm of S. aureus is substantially different from the plasma-free biofilm. Plasma biofilm, especially in the flow-cell system, could be a clinically relevant model to analyze MRSA infections and treatment.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Daptomicina/farmacologia , Farmacorresistência Bacteriana Múltipla , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Vancomicina/farmacologia , Biofilmes/crescimento & desenvolvimento , Meios de Cultura Livres de Soro/química , Meios de Cultura Livres de Soro/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Reologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia
19.
BMC Pharmacol Toxicol ; 20(1): 25, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060599

RESUMO

BACKGROUND: Daptomycin is an important drug used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. A high dose of daptomycin is indicated for an MRSA infection with a minimum inhibitory concentration (MIC) of 1 mg/L for daptomycin. Combination therapies with daptomycin and other antimicrobial agents, including fosfomycin, display in vitro synergism potentially. This study was conducted to investigate the in vitro synergistic effect of daptomycin-based combination therapy against MRSA strains with high daptomycin MIC. METHOD: The synergistic effects of daptomycin in combination with fosfomycin, gentamicin, linezolid, oxacillin, or rifampicin against MRSA with an MIC of 1 mg/L for daptomycin were measured using the microbroth checkerboard assay in vitro. RESULT: A total of 100 MRSA isolates was tested. The synergistic interactions of the drugs were evaluated using the fractional inhibitory concentration index. The MIC values revealed that all isolates (100%) were found to be susceptible to linezolid, 85% to fosfomycin, 8% to gentamicin, 69% to rifampicin, and no isolate was susceptible to oxacillin. The in vitro synergism rates of daptomycin in combination with fosfomycin, oxacillin, gentamicin, linezolid, and rifampicin were 37, 11, 5, 3, and 1%, respectively. CONCLUSION: The combination of daptomycin plus fosfomycin may be an effective therapeutic option for MRSA infection.


Assuntos
Antibacterianos/farmacologia , Daptomicina/farmacologia , Fosfomicina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Sinergismo Farmacológico , Gentamicinas/farmacologia , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Oxacilina/farmacologia , Rifampina/farmacologia
20.
BMC Res Notes ; 12(1): 260, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077228

RESUMO

OBJECTIVES: Methicillin resistant Staphylococcus (S.) aureus colonization is one of the main causes of serious infections in hemodialysis patients. This cross-sectional study was performed to examine prevalence of MRSA colonization and evaluation of risk factors in hemodialysis patients. A total of 560 swab samples from nasal, the skin around catheter and throat were collected from 231 hemodialysis patients in Tabriz. The standard biochemical tests were used for identification of S. aureus isolates. Antimicrobial susceptibility profile was determined against 11 antibiotics by the disk diffusion method. Phenotypic test of S. aureus was performed using novobiocin 30 µg/disc, and methicillin sensitivity test was performed by cefoxitin 30 µg/disc. RESULTS: Overall, 50.65% (118/231) hemodialysis patients were positive for S. aureus which 34.93% (80/231) of patients were MRSA carriage. The MRSA colonization in patients with a catheter (44.06%) was more than individuals utilizing a fistula (24.57%, p = 0.030). Among sampling sites, the highest MRSA was related to nasal samples (30.70%, p < 0.00001). Extra nasal colonization of S. aureus was observed in 12.71% patients. The highest rates of resistance were observed against ampicillin (93.98%) and the highest sensitivity was against linezolid antibiotic (5.42%). These findings highlight the necessity of prophylaxis against S. aureus in individuals under dialysis.


Assuntos
Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Diálise Renal , Adolescente , Adulto , Antibacterianos/farmacologia , Feminino , Humanos , Irã (Geográfico) , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Adulto Jovem
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