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1.
Int J Nanomedicine ; 18: 307-322, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36700146

RESUMO

Background: Successful treatment of infectious bone defect remains a major challenge in the orthopaedic field. At present, the conventional treatment for infectious bone defects is surgical debridement and long-term systemic antibiotic use. It is necessary to develop a new strategy to achieve effective bone regeneration and local anti-infection for infectious bone defects. Methods: Firstly, vancomycin / poly (lactic acid-glycolic acid) sustained release microspheres (VAN/PLGA-MS) were prepared. Then, through the dual-nozzle 3D printing technology, VAN/PLGA-MS was uniformly loaded into the pores of nano-hydroxyapatite (n-HA) and polylactic acid (PLA) scaffolds printed in a certain proportion, and a composite scaffold (VAN/MS-PLA/n-HA) was designed, which can not only promote bone repair but also resist local infection. Finally, the performance of the composite scaffold was evaluated by in vivo and in vitro biological evaluation. Results: The in vitro release test of microspheres showed that the release of VAN/PLGA-MS was relatively stable from the second day, and the average daily release concentration was about 15.75 µg/mL, which was higher than the minimum concentration specified in the guidelines. The bacteriostatic test in vitro showed that VAN/PLGA-MS had obvious inhibitory effect on Staphylococcus aureus ATCC-29213. Biological evaluation of VAN/MS-PLA/n-HA scaffolds in vitro showed that it can promote the proliferation of adipose stem cells. In vivo biological evaluation showed that VAN/MS-PLA/n-HA scaffold could significantly promote bone regeneration. Conclusion: Our research shows that VAN/MS-PLA/n-HA scaffolds have satisfying biomechanical properties, effectively inhibit the growth of Staphylococcus aureus, with good biocompatibility, and effectiveness on repairing bone defects. The VAN/MS-PLA/n-HA scaffold provide the clinic with an application prospect in bone tissue engineering.


Assuntos
Durapatita , Vancomicina , Durapatita/farmacologia , Vancomicina/farmacologia , Tecidos Suporte , Microesferas , Preparações de Ação Retardada/farmacologia , Regeneração Óssea , Poliésteres/farmacologia , Impressão Tridimensional , Osteogênese
2.
Infect Immun ; 91(1): e0042322, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36602380

RESUMO

Staphylococcus aureus (especially methicillin-resistant S. aureus [MRSA]) is frequently associated with persistent bacteremia (PB) during vancomycin therapy despite consistent susceptibility in vitro. Strategic comparisons of PB strains versus those from vancomycin-resolving bacteremia (RB) would yield important mechanistic insights into PB outcomes. Clinical PB versus RB isolates were assessed in vitro for intracellular replication and small colony variant (SCV) formation within macrophages and endothelial cells (ECs) in the presence or absence of exogenous vancomycin. In both macrophages and ECs, PB and RB isolates replicated within lysosome-associated membrane protein-1 (LAMP-1)-positive compartments. PB isolates formed nonstable small colony variants (nsSCVs) in vancomycin-exposed host cells at a significantly higher frequency than matched RB isolates (in granulocyte-macrophage colony-stimulating factor [GM-CSF], human macrophages PB versus RB, P < 0.0001 at 48 h; in ECs, PB versus RB, P < 0.0001 at 24 h). This phenotype could represent one potential basis for the unique ability of PB isolates to adaptively resist vancomycin therapy and cause PB in humans. Elucidating the molecular mechanism(s) by which PB strains form nsSCVs could facilitate the discovery of novel treatment strategies to mitigate PB due to MRSA.


Assuntos
Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Vancomicina/farmacologia , Resistência a Meticilina , Células Endoteliais , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Bacteriemia/tratamento farmacológico , Macrófagos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico
3.
Antimicrob Agents Chemother ; 67(1): e0126422, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36602372

RESUMO

Tunneled central venous catheter (TCVC) related infection remains a challenge in the care of hemodialysis patients. We aimed to determine the best antimicrobial lock therapy (ALT) to eradicate coagulase-negative staphylococci (CoNS) biofilms. We studied the colonization status of the catheter every 30 days by quantitative blood cultures (QBC) drawn through all catheter lumens. Those patients with a significant culture (i.e.,100 to 1,000 CFU/mL) of a CoNS were classified as patients with a high risk of developing catheter-related bloodstream infections (CRBSI). They were assigned to receive daptomycin, vancomycin, teicoplanin lock solution, or the standard of care (SoC) (i.e., heparin lock). The primary endpoint was to compare eradication ability (i.e., negative QBC for 30 days after ending ALT) rates between different locks and the SoC. A second objective was to analyze the correlation between ALT exposure and isolation of CoNS with antimicrobial resistance. Daptomycin lock was associated with a significant higher eradication success than with the SoC: 85% versus 30% (relative risk [RR] = 14, 95% confidence interval [CI] = 2.4 - 82.7); followed by teicoplanin locks with a 83.3% success (RR = 11.7; 95% CI = 2 - 70.2). We observed CoNs isolates with a higher teicoplanin MIC in patients with repeated teicoplanin locks exposure (coefficient = 0.3; 95% CI = 0.11 - 0.47). However, teicoplanin MICs decreased in patients treated with vancomycin locks (coefficient = -0.56; 95% CI = -0.85 - -0.02). Methicillin-resistance decreased with accumulative ALT (RR = 0.82; 95% CI = 0.69 - 0.98). In this study, daptomycin locks achieve the highest eradication rate of CoNS from hemodialysis catheters in vivo.


Assuntos
Anti-Infecciosos , Infecções Relacionadas a Cateter , Cateteres Venosos Centrais , Daptomicina , Humanos , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Vancomicina/farmacologia , Vancomicina/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Teicoplanina/farmacologia , Teicoplanina/uso terapêutico , Coagulase , Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções Relacionadas a Cateter/prevenção & controle , Staphylococcus , Cateteres Venosos Centrais/efeitos adversos , Biofilmes
4.
PeerJ ; 11: e14411, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36684666

RESUMO

Background: Antimicrobial resistance is a global concern. Analysis of sterile fluids is essential because microorganisms are defined as significant in most cases. Blood, cerebrospinal, and pleural fluids are frequently received in the microbiology lab because they are associated with considerable rates of morbi-mortality. Knowledge of epidemiology in these samples is needed to choose proper empirical treatments due to the importance of reducing selection pressure. Methods: We used retrospective laboratory data of blood, CSF, and pleural fluid collected from patients in Mexico between 2019 and 2020. Each laboratory identified the strains and tested susceptibility using its routine methods. For Streptococcus pneumoniae, a comparative analysis was performed with data from the broth microdilution method. Results: Forty-five centers participated in the study, with 30,746 clinical isolates from blood, 2,429 from pleural fluid, and 2,275 from CSF. For blood and CSF, Staphylococcus epidermidis was the most frequent. For blood, among gram negatives, the most frequent was Escherichia coli. Among Enterobacterales, 9.8% of K. pneumoniae were carbapenem-resistant. For S. pneumoniae, similar resistance percentages were observed for levofloxacin, cefotaxime, and vancomycin. For CSF, the most frequent gram-negative was E. coli. In Acinetobacter baumannii, carbapenem resistance was 71.4%. The most frequent species detected for pleural fluid was E. coli; in A. baumannii, carbapenem resistance was 96.3%. Conclusion: Gram-negative bacteria, with E. coli most prevalent, are frequently recovered from CSF, blood, and pleural fluid. In S. pneumoniae, the routine, conventional methods showed good agreement in detecting resistance percentages for erythromycin, levofloxacin, and vancomycin.


Assuntos
Antibacterianos , Vancomicina , Humanos , Antibacterianos/farmacologia , Vancomicina/farmacologia , Levofloxacino , Escherichia coli , Incidência , Estudos Retrospectivos , Bactérias , Carbapenêmicos , Resistência a Medicamentos
5.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675063

RESUMO

Coagulase-negative staphylococci (CoNS) and especially Staphylococcus epidermidis are responsible for health care infections, notably in the presence of foreign material (e.g., venous or central-line catheters). Catheter-related bacteremia (CRB) increases health care costs and mortality. The aim of our study was to evaluate the impact of 15 days of antibiotic exposure (ceftobiprole, daptomycin, linezolid and vancomycin) at sub-inhibitory concentration on the resistance, fitness and genome evolution of 36 clinical strains of S. epidermidis responsible for CRB. Resistance was evaluated by antibiogram, the ability to adapt metabolism by the Biofilm Ring test® and the in vivo nematode virulence model. The impact of antibiotic exposure was determined by whole-genome sequencing (WGS) and biofilm formation experiments. We observed that S. epidermidis strains presented a wide variety of virulence potential and biofilm formation. After antibiotic exposure, S. epidermidis strains adapted their fitness with an increase in biofilm formation. Antibiotic exposure also affected genes involved in resistance and was responsible for cross-resistance between vancomycin, daptomycin and ceftobiprole. Our data confirmed that antibiotic exposure modified bacterial pathogenicity and the emergence of resistant bacteria.


Assuntos
Bacteriemia , Daptomicina , Infecções Estafilocócicas , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Vancomicina/farmacologia , Daptomicina/farmacologia , Staphylococcus epidermidis , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Cateteres/microbiologia , Testes de Sensibilidade Microbiana , Biofilmes
6.
Eur J Clin Microbiol Infect Dis ; 42(2): 177-182, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36502498

RESUMO

Viridans group streptococci (VGS) bloodstream infection (BSI) in neutropenic patients can be a severe complication. A higher prevalence of vancomycin use has been reported due to reduced susceptibility to penicillin. We aimed to assess the impact on mortality of both penicillin minimal inhibitory concentration (MIC) and the use of vancomycin. We conducted a retrospective multicenter study including consecutive neutropenic patients with VGS BSI between 2007 and 2019. Univariable and multivariable analyses were conducted to evaluate risk factors for mortality, including penicillin susceptibility as an independent variable. Non-susceptibility to penicillin was defined as MIC ≥ 0.25. We included 125 neutropenic patients with VGS BSI. Mean age was 53 years and ~ 50% were women. Overall, 30-day mortality rate was 25/125 (20%), and 41 patients (33%) had a VGS isolate non-susceptible to penicillin. In univariable analysis, no significant association was demonstrated between penicillin non-susceptibility and mortality (9/25, 26% vs. 32/100, 32%, p = 0.81). Among patients with a non-susceptible strain, the use of vancomycin was not significantly associated with mortality (empirical, p = 0.103, or definitive therapy, p = 0.491). Factors significantly associated with increased mortality in multivariable analysis included functional status (ECOG > 1, adjusted odds ratio [aOR] 12.53, 95% CI 3.64-43.14; p < 0.0001); allogeneic transplantation (aOR 6.33, 95% CI 1.96-20.46; p = 0.002); and co-pathogen in blood cultures (aOR 3.99, 95% CI 1.34-11.89; p = 0.013). Among neutropenic hemato-oncological patients with VGS BSI, penicillin non-susceptibility and the use of vancomycin were not associated with mortality. Thus, vancomycin should not be used routinely as empirical therapy in neutropenic patients with suspected VGS BSI.


Assuntos
Sepse , Infecções Estreptocócicas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Penicilinas/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/epidemiologia , Vancomicina/farmacologia , Vancomicina/uso terapêutico , Estreptococos Viridans , Sepse/tratamento farmacológico , Testes de Sensibilidade Microbiana
7.
J Adv Res ; 43: 87-96, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36585117

RESUMO

INTRODUCTION: High-dose drug administration for the conventional treatment of inflammatory bowel disease induces cumulative toxicity and serious side effects. Currently, few reports have introduced smart carriers for intestinal inflammation targeting toward the treatment of inflammatory bowel disease. OBJECTIVES: For the unique lysozyme secretory microenvironment of the inflamed intestine, vancomycin-loaded chitosan-polyaniline microgels (CH-PANI MGs) were constructed for lysozyme-triggered VM release. METHODS: Aniline was first grafted to chitosan to form polymers that were crosslinked by glutaraldehyde to achieve CH-PANI MGs using the inverse (water-in-oil) miniemulsion method. Interestingly, CH-PANI MGs exhibit polyampholyte behaviour and display charge-reversible behaviour (positive to negative charges) after treatment with a NaCl solution. RESULTS: The formed negatively charged N-CH-PANI MG aqueous solution is employed to load cationic vancomycin with a satisfactory loading efficiency of 91.3%, which is significantly higher than that of chitosan-based MGs. Moreover, N-CH-PANI MGs present lysozyme-triggered biodegradation and controllable vancomycin release upon the cleavage of glycosidic linkages of chitosan. In the simulated inflammatory intestinal microenvironment, vancomycin is rapidly released, and the cumulative release reaches approximately 76.9%. Remarkably, N-CH-PANI@VM MGs not only exhibit high resistance to harsh gastric acidity but also prevent the premature leakage of vancomycin in the healthy gastrointestinal tract. Encouragingly, the N-CH-PANI@VM MGs show obvious antibacterial activity against Staphylococcus aureus at a relatively low concentration of 20 µg/mL. CONCLUSION: Compared to other pH-responsive carriers used to treat inflammatory bowel disease, the key advantage of lysozyme-responsive MGs is that they further specifically identify healthy and inflammatory intestines, achieving efficient inflammatory bowel disease treatment with few side effects. With this excellent performance, the developed smart MGs might be employed as a potential oral delivery system for inflammatory bowel disease treatment.


Assuntos
Quitosana , Doenças Inflamatórias Intestinais , Microgéis , Humanos , Vancomicina/farmacologia , Muramidase
8.
Mol Pharm ; 20(1): 711-721, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36534730

RESUMO

The treatment of subcutaneous abscesses has been greatly hindered due to the spread of drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Thus, alternative strategies are highly desired to complement conventional antibiotic therapies and surgical intervention. As one of such strategies, applications of nitric oxide (NO) have shown great potential in the treatment of bacteria-induced subcutaneous abscesses by improving the efficacy of many therapeutic methods. However, it is extremely challenging to achieve precise delivery and controlled release because of its gaseous nature. In the present study, an effective strategy was reported in which on demand hydrogen peroxide (H2O2)-activated nitric oxide-releasing vancomycin (Van)-loaded electrostatic complexation (Lipo/Van@Arg) was fabricated. In this system, Van was encapsulated into a negative-charged DSPG/Chol liposome (Lipo/Van) and electrostatically bound with the positive-charged l-arginine (l-Arg). As expected, Lipo/Van@Arg exhibited superior bacterial binding and biofilm penetration abilities. After being in the interior of the biofilms, Lipo/Van@Arg could be triggered by the endogenous H2O2 and effectively release NO. The released NO could exhibit combined antibacterial and biofilm eradication effects with Van. Moreover, an in vivo evaluation using a BALB/c mouse model of subcutaneous abscesses indicated that the combination treatment of NO and Van based on Lipo/Van@Arg could effectively eliminate MRSA from the abscesses, thereby preventing abscess recurrence. In summary, the Lipo/Van@Arg system developed in this study realized controlled delivery and precise release of NO, which had significant clinical implications in the efficient treatment of abscesses.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Vancomicina , Animais , Camundongos , Vancomicina/farmacologia , Peróxido de Hidrogênio/farmacologia , Óxido Nítrico/uso terapêutico , Abscesso/tratamento farmacológico , Eletricidade Estática , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana
9.
J Med Chem ; 66(1): 962-975, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36584344

RESUMO

Infections caused by multidrug-resistant (MDR) bacteria are increasing worldwide, and with limited clinically available antibiotics, it is urgent to develop new antimicrobials to combat these MDR bacteria. Here, a class of novel amphiphilic xanthohumol derivatives were prepared using a building-block approach. Bioactivity assays showed that the molecule IV15 not only exhibited a remarkable antibacterial effect against clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates (MICs: 1-2 µg/mL) but also had the advantages of rapid bactericidal properties, low toxicity, good plasma stability, and not readily inducing bacterial resistance. Mechanistic studies indicated that IV15 has good membrane-targeting ability and can bind to phosphatidylglycerol and cardiolipin in bacterial membranes, thus disrupting the bacterial cell membranes and causing increased intracellular reactive oxygen species and leakage of proteins and DNA, eventually resulting in bacterial death. Notably, IV15 exhibited remarkable in vivo anti-MRSA efficacy, superior to vancomycin, making it a potential candidate to combat MRSA infections.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Vancomicina/farmacologia , Flavonoides/farmacologia , Testes de Sensibilidade Microbiana
10.
Sci Rep ; 12(1): 20921, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463278

RESUMO

Gram-negative bacteria possess intrinsic resistance to glycopeptide antibiotics so these important antibacterial medications are only suitable for the treatment of Gram-positive bacterial infections. At the same time, polymyxins are peptide antibiotics, structurally related to glycopeptides, with remarkable activity against Gram-negative bacteria. With the aim of breaking the intrinsic resistance of Gram-negative bacteria against glycopeptides, a polycationic vancomycin aglycone derivative carrying an n-decanoyl side chain and five aminoethyl groups, which resembles the structure of polymyxins, was prepared. Although the compound by itself was not active against the Gram-negative bacteria tested, it synergized with teicoplanin against Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii, and it was able to potentiate vancomycin against these Gram-negative strains. Moreover, it proved to be active against vancomycin- and teicoplanin-resistant Gram-positive bacteria.


Assuntos
Polimixinas , Teicoplanina , Teicoplanina/farmacologia , Polimixinas/farmacologia , Vancomicina/farmacologia , Glicopeptídeos/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Escherichia coli
11.
Mikrobiyol Bul ; 56(4): 593-605, 2022 Oct.
Artigo em Turco | MEDLINE | ID: mdl-36458707

RESUMO

Staphylococcus aureus is an important human pathogen that causes community and hospital-acquired infections. The role of vancomycin in the treatment of methicillin-resistant S.aureus infections is indisputable. However, vancomycin intermediate susceptible S.aureus (VISA) and heterogeneously VISA (hVISA) isolates, that cause treatment failures during the use of vancomycin, cannot be detected by routine laboratory methods. The gold standard method for the detection of these isolates is the population profile analysis-area under the curve (PAP-AUC) method. In this study, it was aimed to determine the presence of mecA and mecC gene regions that cause methicillin resistance, the clonal relationship between isolates, and the presence of VISA and hVISA. A total 68 methicillin-resistant S.aureus (MRSA) strains were included in this study which were isolated in the microbiology laboratory of the hospital between 2015- 2020. Identification of the isolates were determined by matrix assisted laser desorption ionization-time of flight mass spectrophotometry (VITEK MS, BioMérieux, France). Methicillin resistance was investigated by disk diffusion method using cefoxitin (30 µg, Bioanalyse, Türkiye) disk and vancomycin MIC values were determined by broth microdilution method. mecA and mecC gene regions were investigated by polymerase chain reaction (PCR) method. The presence of VISA and hVISA were investigated by modified agar screening, macro gradient diffusion test and confirmated by PAP-AUC methods, and the clonal relationship between isolates were investigated by pulsed field gel electrophoresis method. The mecA gene region was determined in all isolates, but the mecC gene region was not found in any of the isolates. The MIC50 value of the isolates was determined as 1 µg/mL and the MIC90 value was determined as 2 µg/mL by broth microdilution method. Six VISA and four hVISA suspected strains were detected by a modified agar screening method. Among the isolates identified as suspicious by the modified agar screening method, one isolate was evaluated as VISA and one isolate was evaluated as hVISA by the gold standard PAP-AUC method. No dominant epidemic isolate has been identified by PFGE. As a result, VISA and hVISA were determined in the hospital. The increase in these isolates is a serious concern. For this reason, it is believed that it would be beneficial to investigate the VISA/hVISA ratios in MRSA isolates at certain periods, and to take necessary infection control measures to implement measures and practices to prevent the spread of these isolates in the community and hospital environment.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Staphylococcus aureus Resistente à Vancomicina , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Vancomicina/farmacologia , Ágar , Resistência a Meticilina
12.
Nat Commun ; 13(1): 7718, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513659

RESUMO

Multidrug-resistant organisms (MDRO) are a major threat to public health. MDRO infections, including those caused by vancomycin-resistant Enterococcus (VRE), frequently begin by colonization of the intestinal tract, a crucial step that is impaired by the intestinal microbiota. However, the specific members of the microbiota that suppress MDRO colonization and the mechanisms of such protection are largely unknown. Here, using metagenomics and mouse models that mimic the patients' exposure to antibiotics, we identified commensal bacteria associated with protection against VRE colonization. We further found a consortium of five strains that was sufficient to restrict VRE gut colonization in antibiotic treated mice. Transcriptomics in combination with targeted metabolomics and in vivo assays indicated that the bacterial consortium inhibits VRE growth through nutrient depletion, specifically by reducing the levels of fructose, a carbohydrate that boosts VRE growth in vivo. Finally, in vivo RNA-seq analysis of each strain of the consortium in combination with ex vivo and in vivo assays demonstrated that a single bacterium (Olsenella sp.) could recapitulate the effect of the consortium. Our results indicate that nutrient depletion by specific commensals can reduce VRE intestinal colonization, which represents a novel non-antibiotic based strategy to prevent infections caused by this multidrug-resistant organism.


Assuntos
Infecções por Bactérias Gram-Positivas , Microbiota , Enterococos Resistentes à Vancomicina , Camundongos , Animais , Vancomicina/farmacologia , Frutose/farmacologia , Enterococos Resistentes à Vancomicina/genética , Antibacterianos/farmacologia , Bactérias , Infecções por Bactérias Gram-Positivas/microbiologia
13.
J Med Chem ; 65(24): 16879-16892, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36512751

RESUMO

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continue to endanger public health. Here, we report the synthesis of neolignan isomagnolone (I) and its isomer II, and the preparation of a series of novel neolignan-antimicrobial peptide (AMP) mimic conjugates. Notably, conjugates III5 and III15 exhibit potent anti-MRSA activity in vitro and in vivo, comparable to that of vancomycin, a current effective treatment for MRSA. Moreover, III5 and III15 display not only fast-killing kinetics and low resistance frequency but also low toxicity as well as effects on bacterial biofilms. Mechanism studies reveal that III5 and III15 exhibit rapid bactericidal effects through binding to the phosphatidylglycerol (PG) and cardiolipin (CL) of the bacterial membrane, thereby disrupting the cell membranes and allowing increased reactive oxygen species (ROS) as well as protein and DNA leakage. The results indicate that these neolignan-AMP mimic conjugates could be promising antimicrobial candidates for combating MRSA infections.


Assuntos
Antibacterianos , Peptídeos Antimicrobianos , Lignanas , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Peptídeos Antimicrobianos/síntese química , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Lignanas/síntese química , Lignanas/farmacologia , Lignanas/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacologia , Animais , Camundongos
14.
Molecules ; 27(24)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36558056

RESUMO

Many potent antibiotics fail to treat bacterial infections due to emergence of drug-resistant strains. This surge of antimicrobial resistance (AMR) calls in for the development of alternative strategies and methods for the development of drugs with restored bactericidal activities. In this context, we surmised that identifying aptamers using nucleotides connected to antibiotics will lead to chemically modified aptameric species capable of restoring the original binding activity of the drugs and hence produce active antibiotic species that could be used to combat AMR. Here, we report the synthesis of a modified nucleoside triphosphate equipped with a vancomycin moiety on the nucleobase. We demonstrate that this nucleotide analogue is suitable for polymerase-mediated synthesis of modified DNA and, importantly, highlight its compatibility with the SELEX methodology. These results pave the way for bacterial-SELEX for the identification of vancomycin-modified aptamers.


Assuntos
Aptâmeros de Nucleotídeos , Vancomicina , Vancomicina/farmacologia , DNA Polimerase Dirigida por DNA/metabolismo , DNA , Nucleotídeos , Oligonucleotídeos , Antibacterianos/farmacologia , Técnica de Seleção de Aptâmeros/métodos , Aptâmeros de Nucleotídeos/farmacologia
15.
Int J Mol Sci ; 23(23)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36498843

RESUMO

Staphylococcus aureus implant-associated infections are difficult to treat because of the ability of bacteria to form biofilm on medical devices. Here, the efficacy of Sb-1 to control or prevent S. aureus colonization on medical foreign bodies was investigated in a Galleria mellonella larval infection model. For colonization control assays, sterile K-wires were implanted into larva prolegs. After 2 days, larvae were infected with methicillin-resistant S. aureus ATCC 43300 and incubated at 37 °C for a further 2 days, when treatments with either daptomycin (4 mg/kg), Sb-1 (107 PFUs) or a combination of them (3 x/day) were started. For biofilm prevention assays, larvae were pre-treated with either vancomycin (10 mg/kg) or Sb-1 (107 PFUs) before the S. aureus infection. In both experimental settings, K-wires were explanted for colony counting two days after treatment. In comparison to the untreated control, more than a 4 log10 CFU and 1 log10 CFU reduction was observed on K-wires recovered from larvae treated with the Sb-1/daptomycin combination and with their singular administration, respectively. Moreover, pre-infection treatment with Sb-1 was found to prevent K-wire colonization, similarly to vancomycin. Taken together, the obtained results demonstrated the strong potential of the Sb-1 antibiotic combinatory administration or the Sb-1 pretreatment to control or prevent S. aureus-associated implant infections.


Assuntos
Bacteriófagos , Staphylococcus aureus Resistente à Meticilina , Mariposas , Infecções Estafilocócicas , Animais , Staphylococcus aureus , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Vancomicina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Mariposas/microbiologia , Larva/microbiologia , Testes de Sensibilidade Microbiana
16.
J Infect Public Health ; 15(12): 1396-1402, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36371936

RESUMO

BACKGROUND: The treatment options for vancomycin-resistant Enterococcus (VRE) are limited. A combination of daptomycin (DAP) and ß-lactam (BL) has been suggested; however clinical studies supporting this are lacking. METHODS: Patients with VR E. faecium bacteremia who received ≥ 8 mg/kg daptomycin for ≥ 72 h and initiated ≤ 5 days of culture collection between 2010 and 2021 were included. DAP+BL was defined as receiving BL for ≥ 24 h and within 24 h of DAP initiation. The primary endpoint was a composite clinical success (neither 14-day mortality, microbiological failure, nor change in the anti-VRE regimen). Outcomes were analyzed using multivariable logistic regression and augmented inverse probability weighting (AIPW). RESULTS: A total of 430 patients were enrolled (DAP, n = 45; DAP+BL, n = 385). Clinical success was achieved in 19 (42.2%) patients in the DAP group and 244 (63.4%) in the DAP+BL group [adjusted odds ratio, 3.19; 95% confidence interval (CI) 1.61-6.33; P = 0.001]. Marginal analysis showed that the efficacy of DAP+BL was particularly significant with DAP dose ≥ 9 mg/kg and DAP minimum inhibitory concentration (MIC) ≥ 2 mg/L. With the balance of AIPW, standardized mean clinical success rates for DAP and DAP+BL 37.3% and 63.5%, respectively. The difference between DAP+BL and DAP was of 26.2% in favor of DAP+BL (95% CI, 10.0-42.3%; P = 0.001). CONCLUSIONS: DAP+BL was associated with a significantly higher rate of compositive clinical success than DAP for treatment of VR E. faecium bacteremia. The study suggested BL in combination with high-dose DAP for VR E. faecium bacteremia treatment, especially when VRE showed a high DAP MIC.


Assuntos
Bacteriemia , Daptomicina , Enterococcus faecium , Enterococos Resistentes à Vancomicina , Humanos , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Vancomicina/farmacologia , Vancomicina/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Bacteriemia/microbiologia , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Monobactamas/farmacologia , Monobactamas/uso terapêutico
17.
Microb Pathog ; 173(Pt A): 105860, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36341845

RESUMO

The increasing prevalence of vancomycin-resistant Enterococcus faecium, along with the ability of this bacterium to form biofilm on biotic surfaces and medical devices, has created a serious challenge. Therefore, the development of new antibacterial agents is an urgent need. In this study, curcumin carbon dots (Cur-CDs) were synthesized by a one-step hydrothermal method, and its antibacterial and antibiofilm effects were investigated. By broth microdilution method, the minimal inhibitory concentration (MIC) against vancomycin-resistant and sensitive clinical isolates of Enterococcus faecium (two clinical isolates in total) and standard strain of Enterococcus faecalis ATCC 29212 was determined, which were 1000, 1000, and 125 µg/ml, respectively. The inhibitory effect of Cur-CDs on biofilm formation of vancomycin-resistant E. faecium clinical isolates were evaluated by microtiter plate assay. Cur-CDs (1000 µg/ml) significantly prevented (p = 0.009) the biofilm formation of E. faecium isolates. Real-time PCR results showed that Cur-CDs (1000 µg/ml) significantly downregulated the expression of esp and gelE genes (p = 0.001 and p = 000000002, respectively) in clinical isolates of E. faecium, while Cur-CDs did not affect acm gene expression (p = 0.086). This study revealed that Cur-CDs can be effective antibacterial and antibiofilm agents against vancomycin-resistant and biofilm producer E. faecium, which makes them interesting candidates for treating or preventing bacterial infections.


Assuntos
Curcumina , Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Humanos , Curcumina/farmacologia , Vancomicina/farmacologia , Carbono , Fatores de Virulência/genética , Enterococcus faecalis , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Biofilmes , Infecções por Bactérias Gram-Positivas/microbiologia
18.
PLoS One ; 17(11): e0277287, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36350834

RESUMO

Staphylococcus epidermis is one of the most frequent causes of device-associated infections due to biofilm formation. Current reports noted that subinhibitory concentrations of antibiotics induce biofilm production in some bacteria. Accordingly, we evaluated the effect of exposure of different subinhibitory concentrations of cloxacillin, cefazolin, clindamycin, and vancomycin on the biofilm formation of methicillin-resistant S. epidermidis (MRSE). Antimicrobial susceptibility testing and minimum inhibitory/bactericidal concentration of antimicrobial agents were determined. MRSE isolates were selected, and their biofilm formation ability was evaluated. The effect of subinhibitory concentrations of cloxacillin, cefazolin, clindamycin, and vancomycin, antibiotics selected among common choices in the clinic, on MRSE biofilm formation was determined by the microtitre method. Besides, the effect of subinhibitory concentrations of cloxacillin, cefazolin, clindamycin, and vancomycin on the expression of the biofilm-associated genes icaA and atlE was evaluated by Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR). Antimicrobial susceptibility patterns of MRSE strains showed a high level of resistance as follows: 80%, 53.3%, 33.3%, 33.3%, and 26.6%, for erythromycin, trimethoprim-sulfamethoxazole, tetracycline, clindamycin, and gentamicin, respectively. Besides, 73.3% of S. epidermidis strains were Multidrug-resistant (MDR). Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were in the range of 0.5 to512 µg/mL and 1 to1024 µg/mL for cloxacillin, 0.125 to256 µg/mL and 1 to512 µg/mL for cefazolin, 0.125 to64 µg/mL and 4 to>1024 µg/mL for clindamycin, and 2 to32 µg/mL and 4 to32 µg/mL for vancomycin, respectively. The findings showed that subinhibitory concentrations of cloxacillin, cefazolin, and clindamycin induce biofilm production in MRSE strains. In particular, the OD values of strains were in the range of 0.09-0.95, 0.05-0.86, and 0.06-1 toward cloxacillin, cefazolin, and clindamycin, respectively. On the other hand, exposure to subinhibitory vancomycin concentrations did not increase the biofilm formation in MRSE strains. The findings also demonstrated that sub-MIC of antibiotics up-regulated biofilm-associated genes. In particular, atlE and icaA were up-regulated 0.062 to 1.16 and 0.078 to 1.48 folds, respectively, for cloxacillin, 0.11 to 0.8, and 0.1 to 1.3 folds for cefazolin, 0.18 to 0.98, and 0.19 to 1.4 folds, respectively, for clindamycin. In contrast, the results showed that sub-MIC of vancomycin did not increase the biofilm-associated genes. These findings overall show that exposure to sub-MIC of traditional antibiotics can cause biofilm induction in MRSE, thereby increasing the survival and persistence on various surfaces that worsen the condition of comorbid infections.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus epidermidis , Cefazolina/farmacologia , Clindamicina/farmacologia , Vancomicina/farmacologia , Resistência a Meticilina , Cloxacilina , Infecções Estafilocócicas/microbiologia , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes
19.
J Med Chem ; 65(22): 15312-15326, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36331380

RESUMO

Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant Enterococci (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer 5 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer 5 can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 5 downregulates vancomycin-mediated transcriptional activation of the vanHAX gene cluster and does not allow VSE to develop vancomycin resistance until 100 generations. Therefore, this study, for the first time, presents a bacterial membrane-targeting amphiphile that can mitigate VRE infections and inhibit the emergence of vancomycin resistance.


Assuntos
Infecções por Bactérias Gram-Positivas , Enterococos Resistentes à Vancomicina , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ácido Cólico/farmacologia , Infecções por Bactérias Gram-Positivas/microbiologia , Testes de Sensibilidade Microbiana , Óperon , Vancomicina/farmacologia , Resistência a Vancomicina/genética , Enterococos Resistentes à Vancomicina/genética , Farmacorresistência Bacteriana/genética
20.
ACS Nano ; 16(11): 19491-19508, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36321923

RESUMO

Chronic wounds are characterized by long-term inflammation and persistent infection, which make them difficult to heal. Therefore, an urgent desire is to develop a multifunctional wound dressing that can prevent wound infection and promote wound healing by creating a favorable microenvironment. In this study, a curcumin-based metal-organic framework (QCSMOF-Van), loaded with vancomycin and coated with quaternary ammonium salt chitosan (QCS), was prepared. Multifunctional composite hydrogels were conveniently synthesized by combining methacrylic anhydride modified gelatin and methacrylic anhydride modified oxidized sodium alginate with QCSMOF-Van through radical polymerization and Schiff base reaction. It is important to note that the QCSMOF-Van could capture bacteria through the positive charges on the surface of QCS. In this process, due to the synergistic effect of broad-spectrum antibacterial Zn2+ and vancomycin, the metabolism of bacteria was well inhibited, and the efficient capturing and rapid killing of bacteria were achieved. The QCSMOF-Van hydrogels could precisely regulate the balance of M1/M2 phenotypes of macrophages, thereby promoting the regeneration of nerves and blood vessels, which promotes the rapid healing of chronic wounds. This advanced cascade management strategy for tissue regeneration highlights the potential of multifunctional composite hydrogels in chronic wound dressings.


Assuntos
Quitosana , Infecção dos Ferimentos , Humanos , Hidrogéis/farmacologia , Vancomicina/farmacologia , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico , Bactérias , Quitosana/farmacologia , Antibacterianos/farmacologia , Anidridos/farmacologia
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