RESUMEN
Osteomyelitis (OM) is a progressive, inflammatory infection of bone caused predominately by Staphylococcus aureus. Herein, we engineered an antibiotic-eluting collagen-hydroxyapatite scaffold capable of eliminating infection and facilitating bone healing. An iterative freeze-drying and chemical crosslinking approach was leveraged to modify antibiotic release kinetics, resulting in a layered dual-release system whereby an initial rapid release of antibiotic to clear infection was followed by a sustained controlled release to prevent reoccurrence of infection. We observed that the presence of microbial collagenase accelerated antibiotic release from the crosslinked layer of the scaffold, indicating that the material is responsive to microbial activity. As exemplar drugs, vancomycin and gentamicin-eluting scaffolds were demonstrated to be bactericidal, and supported osteogenesis in vitro. In a pilot murine model of OM, vancomycin-eluting scaffolds were observed to reduce S. aureus infection within the tibia. Finally, in a rabbit model of chronic OM, gentamicin-eluting scaffolds both facilitated radial bone defect healing and eliminated S. aureus infection. These results show that antibiotic-eluting collagen-hydroxyapatite scaffolds are a one-stage therapy for OM, which when implanted into infected bone defects simultaneously eradicate infection and facilitate bone tissue healing.
Asunto(s)
Antibacterianos , Gentamicinas , Osteomielitis , Infecciones Estafilocócicas , Staphylococcus aureus , Andamios del Tejido , Animales , Andamios del Tejido/química , Antibacterianos/farmacología , Antibacterianos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Osteomielitis/tratamiento farmacológico , Conejos , Staphylococcus aureus/efectos de los fármacos , Gentamicinas/farmacología , Gentamicinas/administración & dosificación , Gentamicinas/química , Gentamicinas/uso terapéutico , Ratones , Vancomicina/farmacología , Vancomicina/química , Vancomicina/administración & dosificación , Durapatita/química , Cinética , Cicatrización de Heridas/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Colágeno/química , FemeninoRESUMEN
Bacteria-infected wounds pose challenges to healing due to persistent infection and associated damage to nerves and vessels. Although sonodynamic therapy can help kill bacteria, it is limited by the residual oxidative stress, resulting in prolonged inflammation. To tackle these barriers, novel 4 octyl itaconate-coated Li-doped ZnO/PLLA piezoelectric composite microfibers are developed, offering a whole-course "targeted" treatment under ultrasound therapy. The inclusion of Li atoms causes the ZnO lattice distortion and increases the band gap, enhancing the piezoelectric and sonocatalytic properties of the composite microfibers, collaborated by an aligned PLLA conformation design. During the infection and inflammation stages, the piezoelectric microfibers exhibit spatiotemporal-dependent therapeutic effects, swiftly eliminating over 94.2 % of S. aureus within 15 min under sonodynamic therapy. Following this phase, the microfibers capture reactive oxygen species and aid macrophage reprogramming, restoring mitochondrial function, achieving homeostasis, and shortening inflammation cycles. As the wound progresses through the healing stages, bioactive Zn2+ and Li + ions are continuously released, improving cell recruitment, and the piezoelectrical stimulation enhances wound recovery with neuro-vascularization. Compared to commercially available dressings, our microfibers accelerate the closure of rat wounds (Φ = 15 mm) without scarring in 12 days. Overall, this "one stone, four birds" wound management strategy presents a promising avenue for infected wound therapy.
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Terapia por Ultrasonido , Cicatrización de Heridas , Animales , Cicatrización de Heridas/efectos de los fármacos , Terapia por Ultrasonido/métodos , Ratas Sprague-Dawley , Ratas , Staphylococcus aureus/efectos de los fármacos , Óxido de Zinc/química , Ratones , Estimulación Eléctrica , Masculino , Infecciones Estafilocócicas/terapia , Poliésteres/química , Especies Reactivas de Oxígeno/metabolismo , Terapia por Estimulación Eléctrica/métodos , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
Frequent occurrence of wound infection caused by multiple-resistant bacteria (MRB) has posed a serious challenge to the current healthcare system relying on antibiotics. The development of novel antimicrobial materials with high safety and efficacy to heal wound infection is of great importance in combating this crisis. Herein, we prepared a promising antibacterial hydrogel by cross-linking ferrous ions (Fe2+) with the deprotonated carboxyl anion in sodium alginate (Na-ALG) to cure wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Interestingly, ferrous-modified Na-ALG (Fe-ALG) hydrogel demonstrated better properties compared to the traditional Na-ALG-based hydrogels, including injectability, self-healing, appropriate fluidity, high-water retention, potent MRSA-killing efficacy, and excellent biocompatibility. Importantly, the addition of Fe2+ enhances the antibacterial efficacy of the Na-ALG hydrogel, enabling it to effectively eliminate MRSA and accelerate the healing of antibiotic-resistant bacterial-infected wounds in a remarkably short period (10 days). This modification not only facilitates wound closure and fur generation, but also mitigates systemic inflammation, thereby effectively impeding the spread of MRSA to the lungs. Taken together, Fe-ALG hydrogel is a promising therapeutic material for treating wound infections by Staphylococcus aureus, especially by antibiotic-resistant strains like MRSA.
Asunto(s)
Alginatos , Antibacterianos , Compuestos Ferrosos , Hidrogeles , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Cicatrización de Heridas , Infección de Heridas , Alginatos/química , Alginatos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Animales , Infecciones Estafilocócicas/tratamiento farmacológico , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , MasculinoRESUMEN
Orbital cellulitis is a common ophthalmologic consultation and has numerous risk factors; however, one that is seldomly encountered is chronic cocaine use. We describe a case of a 63-year-old man with a history of HIV and cocaine use who presented with OD pain, proptosis, and blurred vision. CT imaging revealed extensive erosions throughout the nasal septum, bilateral turbinates, ethmoid sinuses, and loss of the right medial orbital wall. The patient was treated empirically with broad-spectrum antibiotics, and a nasal biopsy and culture grew Staphylococcus aureus. After treatment with IV antibiotics, the patient's visual acuity returned to baseline with resolution of extraocular motility limitations. Although nasal erosions are a well-described sequela of cocaine use, full-thickness osseous defects of the orbital wall are rare and represent late-stage complications of cocaine-induced destructive midline lesions. Orbital cellulitis is a very rare complication in the setting of cocaine-induced destructive midline lesions. Clinicians should be aware of the link between cocaine use, rhino-orbital abnormalities, and orbital cellulitis.
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Trastornos Relacionados con Cocaína , Celulitis Orbitaria , Tomografía Computarizada por Rayos X , Humanos , Masculino , Persona de Mediana Edad , Trastornos Relacionados con Cocaína/complicaciones , Celulitis Orbitaria/diagnóstico , Celulitis Orbitaria/inducido químicamente , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Bacterianas del Ojo/diagnóstico , Antibacterianos/efectos adversos , Staphylococcus aureus/aislamiento & purificación , Cocaína/efectos adversosRESUMEN
The rise of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge in clinical settings due to its ability to evade conventional antibiotic treatments. This overview explores the potential of immunomodulatory strategies as alternative therapeutic approaches to combat MRSA infections. Traditional antibiotics are becoming less effective, necessitating innovative solutions that harness the body's immune system to enhance pathogen clearance. Recent advancements in immunotherapy, including the use of antimicrobial peptides, phage therapy, and mechanisms of immune cells, demonstrate promise in enhancing the body's ability to clear MRSA infections. However, the exact interactions between these therapies and immunomodulation are not fully understood, underscoring the need for further research. Hence, this review aims to provide a broad overview of the current understanding of non-traditional therapeutics and their impact on immune responses, which could lead to more effective MRSA treatment strategies. Additionally, combining immunomodulatory agents with existing antibiotics may improve outcomes, particularly for immunocompromised patients or those with chronic infections. As the landscape of antibiotic resistance evolves, the development of effective immunotherapeutic strategies could play a vital role in managing MRSA infections and reducing reliance on traditional antibiotics. Future research must focus on optimizing these approaches and validating their efficacy in diverse clinical populations to address the urgent need for effective MRSA management strategies.
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Inmunomodulación , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Humanos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/terapia , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Inmunoterapia/métodos , Terapia de Fagos/métodos , Animales , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/uso terapéutico , Factores InmunológicosRESUMEN
Introduction. Staphylococcus aureus is a leading agent in community-acquired bacteraemia (CAB) and has been linked to elevated mortality rates and methicillin resistance in Costa Rica.Gap statement and aim. To update and enhance previous data obtained in this country, we analysed the clinical manifestations of 54 S. aureus CAB cases in a tertiary hospital and delineated the sequence types (STs), virulome, and resistome of the implicated isolates.Methodology. Clinical information was retrieved from patient files. Antibiotic susceptibility profiles were obtained with disc diffusion and automated phenotypic tests. Genomic data were exploited to type the isolates and for detection of resistance and virulence genes.Results. Primary infections predominantly manifested as bone and joint infections, followed by skin and soft tissue infections. Alarmingly, 70% of patients continued to exhibit positive haemocultures beyond 48 h of treatment modification, with nearly a quarter requiring mechanical ventilation or developing septic shock. The 30-day mortality rate reached an alarming 40%. More than 60% of the patients were found to have received suboptimal or inappropriate antibiotic treatment, and there was an alarming tendency towards the overuse of third-generation cephalosporins as empirical treatment. Laboratory tests indicated elevated creatinine levels, leukocytosis, and bandaemia within the first 24 h of hospitalization. However, most showed improvement after 48 h. The isolates were categorized into 13 STs, with a predominance of representatives from the clonal complexes CC72 (ST72), CC8 (ST8), CC5 (ST5, ST6), and CC1 (ST188). Twenty-four isolates tested positive for mecA, with ST72 strains accounting for 20. In addition, we detected genes conferring acquired resistance to aminoglycosides, MLSB antibiotics, trimethoprim/sulfamethoxazole, and mutations for fluoroquinolone resistance in the isolate collection. Genes associated with biofilm formation, capsule synthesis, and exotoxin production were prevalent, in contrast to the infrequent detection of enterotoxins or exfoliative toxin genes.Conclusions. Our findings broaden our understanding of S. aureus infections in a largely understudied region and can enhance patient management and treatment strategies.
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Antibacterianos , Bacteriemia , Infecciones Comunitarias Adquiridas , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas , Staphylococcus aureus , Centros de Atención Terciaria , Humanos , Costa Rica/epidemiología , Centros de Atención Terciaria/estadística & datos numéricos , Infecciones Comunitarias Adquiridas/microbiología , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/mortalidad , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/mortalidad , Bacteriemia/microbiología , Bacteriemia/epidemiología , Bacteriemia/mortalidad , Bacteriemia/tratamiento farmacológico , Masculino , Staphylococcus aureus/genética , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Persona de Mediana Edad , Femenino , Anciano , Adulto , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Anciano de 80 o más Años , Adulto Joven , Adolescente , Factores de Virulencia/genética , NiñoRESUMEN
In March 2023, our pediatric intensive care unit (PICU) retrospectively examined six cases of pediatric necrotizing tracheobronchitis (NTB), focusing on co-infections with influenza A virus (IAV) and Staphylococcus aureus (S. aureus). This study aimed to elucidate NTB's clinical characteristics, diagnostics, and therapeutic approaches. Diagnostics included symptom assessment, microbiological testing that confirmed all patients were positive for IAV H1N1 with a predominant S. aureus co-infection, and bronchoscopy. The patients predominantly exhibited fever, cough, and dyspnea. Laboratory analysis revealed decreased lymphocyte counts and elevated infection markers like C-reactive protein and procalcitonin. Chest computed tomography (CT) scans detected tracheobronchial obstructions in half of the cases, while bronchoscopy showed severe mucosal congestion, edema, necrosis, and purulent-hemorrhagic exudates. Treatments encompassed comprehensive strategies like oxygen therapy, intubation, bronchoscopic interventions, thoracentesis, oseltamivir, and a regimen of antibiotics. Our findings suggested potential correlations between clinical markers, notably lymphocyte count and procalcitonin, and clinical interventions such as the number of rescues and intensive care unit (ICU) duration. This research highlights the importance of early detection and the role of bronchoscopy and specific markers in assessing NTB, advocating for continued research in larger cohorts to better understand its clinical trajectory and refine treatment approaches for this challenging pediatric disease.
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Bronquitis , Coinfección , Gripe Humana , Infecciones Estafilocócicas , Staphylococcus aureus , Traqueítis , Humanos , Coinfección/diagnóstico , Masculino , Femenino , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/complicaciones , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Preescolar , Traqueítis/diagnóstico , Traqueítis/microbiología , Traqueítis/complicaciones , Bronquitis/diagnóstico , Bronquitis/microbiología , Bronquitis/complicaciones , Estudios Retrospectivos , Staphylococcus aureus/aislamiento & purificación , Lactante , Niño , Broncoscopía/métodos , Unidades de Cuidado Intensivo Pediátrico , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Necrosis , Virus de la Influenza A/aislamiento & purificaciónRESUMEN
BACKGROUND: Staphylococcus aureus is an infectious bacterium that is frequently found in healthcare settings and the community. This study aimed to prepare rutin-loaded chitosan nanoparticles (Rut-CS NPs) and assess their antibacterial activity against pathogenic strains of S. aureus. RESULTS: The synthesized Rut-CS NPs exhibited an amorphous morphology with a size ranging from 160 to 240 nm and a zeta potential of 37.3 mV. Rut-CS NPs demonstrated significant antibacterial activity against S. aureus strains. Following exposure to Rut-CS NPs, the production of staphyloxanthin pigment decreased by 43.31-89.63%, leading to increased susceptibility of S. aureus to hydrogen peroxide. Additionally, visual inspection of cell morphology indicated changes in membrane integrity and permeability upon Rut-CS NPs exposure, leading to a substantial increase (107.07-191.08%) in cytoplasmic DNA leakage in the strains. Furthermore, ½ MIC of Rut-CS NPs effectively inhibited the biofilm formation (22.5-37.5%) and hemolytic activity (69-82.59%) in the S. aureus strains. CONCLUSIONS: Our study showcases that Rut-CS NPs can serve as a novel treatment agent to combat S. aureus infections by altering cell morphology and inhibiting virulence factors of S. aureus.
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Antibacterianos , Biopelículas , Quitosano , Pruebas de Sensibilidad Microbiana , Nanopartículas , Rutina , Staphylococcus aureus , Xantófilas , Staphylococcus aureus/efectos de los fármacos , Quitosano/farmacología , Quitosano/química , Rutina/farmacología , Rutina/química , Nanopartículas/química , Antibacterianos/farmacología , Antibacterianos/química , Biopelículas/efectos de los fármacos , Xantófilas/farmacología , Xantófilas/química , Hemólisis/efectos de los fármacos , Factores de Virulencia , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Humanos , Peróxido de Hidrógeno/farmacologíaRESUMEN
Staphylococcus aureus can develop antibiotic resistance and evade immune responses, causing infections in different body sites. However, the metabolic changes underlying this process are poorly understood. A variant strain, C1V, was derived from the parental strain C1 by exposing it to increasing concentrations of vancomycin in vitro. C1V exhibited a vancomycin-intermediate phenotype and physiological changes compared to C1. It showed higher survival rates than C1 when phagocytosed by Raw264.7 cells. Metabolomics analysis identified significant metabolic differences pre- and post-induction (C1 + SC1 vs. C1V + SC1V: 201 metabolites) as well as pre- and post-phagocytosis (C1 vs. SC1: 50 metabolites; C1V vs. SC1V: 95 metabolites). The variant strain had distinct morphological characteristics, decreased adhesion ability, impaired virulence, and enhanced resistance to phagocytosis compared to the parental strain. Differential metabolites may contribute to S. aureus ' resistance to antibiotics and phagocytosis, offering insights into potential strategies for altering vancomycin nonsusceptibility and enhancing phagocyte killing by manipulating bacterial metabolism.
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Antibacterianos , Metabolómica , Fagocitosis , Staphylococcus aureus , Vancomicina , Vancomicina/farmacología , Ratones , Animales , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Fagocitosis/efectos de los fármacos , Células RAW 264.7 , Antibacterianos/farmacología , Virulencia , Infecciones Estafilocócicas/microbiología , Pruebas de Sensibilidad Microbiana , Resistencia a la Vancomicina/genética , Metaboloma/efectos de los fármacos , Adhesión Bacteriana/efectos de los fármacos , Adaptación FisiológicaRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen that can cause severe bacterial pneumonia. Amygdalin is the main active pharmaceutical ingredient of bitter almond, which has broad-spectrum antibacterial, anti-inflammatory, anti-oxidation and immunomodulatory effects. It is also the main ingredient of Yinhua Pinggan granule, which is commonly used to moisten the lung and relieve cough. However, little is known about the effects of amygdalin on MRSA. In this study, we found that amygdalin exhibited good antimicrobial activity in vitro against MRSA. Amygdalin has a protective effect on MRSA infected cells, and the effect is better when combined with levofloxacin. It also can reduce the adhesion and invasion of MRSA to cells. Amygdalin has anti-inflammatory and antioxidant effects, which can significantly reduce the increase of inflammatory factors and the production of ROS caused by infection. The protective mechanism of amygdalin on cells may be related to inhibiting the expression of NLRP3, ASC and IL-1ß pyroptosis pathways. Taken together, our study suggests that amygdalin exerts antibacterial effects by affecting biofilm formation, the expression of virulence factors, and drug resistance genes. Amygdalin combined with levofloxacin has a protective effect on A549 cells infected with MRSA, and the mechanism may be related to the inhibition of inflammatory response, oxidative damage and pyroptosis.
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Amigdalina , Antibacterianos , Inflamación , Staphylococcus aureus Resistente a Meticilina , Estrés Oxidativo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Amigdalina/farmacología , Humanos , Estrés Oxidativo/efectos de los fármacos , Células A549 , Antibacterianos/farmacología , Inflamación/tratamiento farmacológico , Inflamación/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Células Epiteliales/metabolismo , Pulmón/microbiología , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Biopelículas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Levofloxacino/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiologíaRESUMEN
INTRODUCTION: Tropical myositis - also known as pyomyositis - is a subacute, primary infection of skeletal muscle. Long considered a diagnosis exclusive to tropical climates, recently it has been reported increasingly in historically nontropical climates. We present a case of tropical myositis in Madison, Wisconsin, occurring in a febrile type 1 diabetic patient without travel or known exposure. CASE PRESENTATION: A 35-year-old male with a history of von Willebrand disease, type 1 diabetes, and financial insecurity resulting in insulin rationing presented with 2 weeks of generalized weakness. On exam, he had a multitude of large, erythematous "bumps" across his body, which had been increasing in size for more than 2 weeks. His blood glucose was 518, with leukocytosis and labs supportive of diabetic ketoacidosis. Computed tomography revealed extensive intramuscular and subcutaneous abscesses of the left chest, bilateral erector spinae, right gluteal muscles, bilateral thighs, left leg, and left upper and lower arm. Broad-spectrum antibiotics were initiated, as was treatment for diabetic ketoacidosis. Blood and urine cultures revealed oxacillin-susceptible Staphylococcus aureus. After clinical stabilization, he underwent initial incision and drainage of the abscesses. His condition would require 14 more operative incision and drainage procedures and wound closure attempts before he was discharged to a rehab facility after more than a month-long hospitalization. DISCUSSION: Severe tropical myositis is associated with high morbidity and high use of health care resources. The exponential rise in cases in the United States in recent years risks further stressing an already-burdened health care system. We explore potential causes of the increase in cases of tropical myositis in nontropical regions, including increasing rates of diabetes and poverty and climate change. Recent data suggest that the large majority of tropical myositis cases are caused by Panton-Valentine leukocidin toxin-producing Staphylococcus aureus strains. There is a theoretical mitigation of disease severity when patients receive early protein synthesis inhibitor antibiotic treatment, though these findings are limited to case reports and observational studies and lack controlled clinical trials. This case highlights the need for early identification, antibiotic administration, and surgical source control in suspected cases of tropical myositis.
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Diabetes Mellitus Tipo 1 , Piomiositis , Humanos , Masculino , Diabetes Mellitus Tipo 1/complicaciones , Adulto , Piomiositis/diagnóstico , Piomiositis/tratamiento farmacológico , Piomiositis/terapia , Diagnóstico Diferencial , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/tratamiento farmacológico , Wisconsin , Antibacterianos/uso terapéutico , Fiebre/etiología , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
In response to the escalating antibiotic resistance in multidrug-resistant pathogens, we propose an innovative phagemid-based capsid system to generate CRISPR-Cas13a-loaded antibacterial capsids (AB-capsids) for targeted therapy against multidrug-resistant Staphylococcus aureus. Our optimized phagemid system maximizes AB-capsid yield and purity, showing a positive correlation with phagemid copy number. Notably, an 8.65-fold increase in copy number results in a 2.54-fold rise in AB-capsid generation. Phagemids carrying terL-terS-rinA-rinB (prophage-encoded packaging site genes) consistently exhibit high packaging efficiency, and the generation of AB-capsids using lysogenized hosts with terL-terS deletion resulted in comparatively lower level of wild-type phage contamination, with minimal compromise on AB-capsid yield. These generated AB-capsids selectively eliminate S. aureus strains carrying the target gene while sparing non-target strains. In conclusion, our phagemid-based capsid system stands as a promising avenue for developing sequence-specific bactericidal agents, offering a streamlined approach to combat antibiotic-resistant pathogens within the constraints of efficient production and targeted efficacy.
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Antibacterianos , Sistemas CRISPR-Cas , Cápside , Staphylococcus aureus Resistente a Meticilina , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Cápside/metabolismo , Cápside/efectos de los fármacos , Antibacterianos/farmacología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs) with Methicillin-Resistant S. aureus (MRSA) strains being a major contributor in both community and hospital settings. S. aureus relies on metabolic diversity and a large repertoire of virulence factors to cause disease. This includes α-hemolysin (Hla), an integral player in tissue damage found in various models, including SSTIs. Previously, we identified a role for the Spx adapter protein, YjbH, in the regulation of several virulence factors and as an inhibitor of pathogenesis in a sepsis model. In this study, we found that YjbH is critical for tissue damage during SSTI, and its absence leads to decreased proinflammatory chemokines and cytokines in the skin. We identified no contribution of YjbI, encoded on the same transcript as YjbH. Using a combination of reporters and quantitative hemolysis assays, we demonstrated that YjbH impacts Hla expression and activity both in vitro and in vivo. Additionally, expression of Hla from a non-native promoter reversed the tissue damage phenotype of the ΔyjbIH mutant. Lastly, we identified reduced Agr activity as the likely cause for reduced Hla production in the ΔyjbH mutant. This work continues to define the importance of YjbH in the pathogenesis of S. aureus infection as well as identify a new pathway important for Hla production.
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Proteínas Bacterianas , Toxinas Bacterianas , Regulación Bacteriana de la Expresión Génica , Proteínas Hemolisinas , Staphylococcus aureus , Transactivadores , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/inmunología , Staphylococcus aureus/genética , Ratones , Animales , Transactivadores/genética , Transactivadores/metabolismo , Infecciones Cutáneas Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/inmunología , Infecciones Cutáneas Estafilocócicas/patología , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/inmunología , Piel/microbiología , Piel/patología , Piel/inmunología , Factores de Virulencia/genética , Humanos , Infecciones de los Tejidos Blandos/microbiología , Infecciones de los Tejidos Blandos/inmunología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citocinas/metabolismo , Citocinas/inmunología , Citocinas/genéticaRESUMEN
Staphylococcus aureus infections are hard to treat due to the emergence of antibiotic resistant strains, as well as their ability to form biofilms. The MazEF toxin-antitoxin system is thought play a role in bacterial biofilm phenotype as well as antibiotic resistance. In S. aureus, the physiologic function of the mazEF gene in the disease transition from acute to chronic infection is not well understood. In methicillin resistant S. aureus (MRSA), loss of mazF expression results in loss of resistance to first generation cephalosporins. mazF::tn displayed sensitivity while the isogenic wild type (WT) remained resistant. mazF::tn displayed significantly increased growth of biofilms on metal implants over 48 h compared to WT and the complemented transposon mutant. mazF::tn biofilms displayed significantly decreased antibiotic tolerance to vancomycin and cefazolin in comparison to WT and complement biofilms. Mice given mazF::tn in a sepsis model displayed less abscess burden and increased survival (100%) when treated with cefazolin compared to WT bacteremia treated with cefazolin (20%). mazF::tn periprosthetic joint infections displayed increased biofilm burden at acute time points and decreased biofilm burden at chronic time points. Our data suggests MazEF in MRSA is responsible for controlling growth of biofilms, antibiotic tolerance, and influence chronic infections in vivo.
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Antibacterianos , Biopelículas , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/fisiología , Animales , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Antibacterianos/farmacología , Ratones , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Pruebas de Sensibilidad Microbiana , Modelos Animales de Enfermedad , Vancomicina/farmacología , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Cefazolina/farmacología , FemeninoRESUMEN
Antibacterial resistance requires an advanced strategy to increase the efficacy of current therapeutics in addition to the synthesis of new generations of antibiotics. In this study, copper oxide nanoparticles (CuO-NPs) were green synthesized using Moringa oleifera root extract. CuO-NPs fabricated into a form of aspartic acid-ciprofloxacin-polyethylene glycol coated copper oxide-nanotherapeutics (CIP-PEG-CuO) to improve the antibacterial activity of NPs and the efficacy of the drug with controlled cytotoxicity. These NPs were charachterized by Fourier transform infrared spectroscopy (FTIR), x-rays diffraction spectroscopy (XRD), scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). Antibacterial screening and bacterial chemotaxis investigations demonstrated that CIP-PEG-CuO NPs show enhanced antibacterial potential against Gram-positive and Gram-negative clinically isolated pathogenic bacterial strains as compared to CuO-NPs. In ex-vivo cytotoxicity CIP-PEG-CuO-nano-formulates revealed 88% viability of Baby Hamster Kidney 21 cell lines and 90% RBCs remained intact with nano-formulations during hemolysis assay. An in-vivo studies on animal models show that Staphylococcus aureus were eradicated by this newly developed formulate from the infected skin and showed wound-healing properties. By using specially designed nanoparticles that are engineered to precisely transport antimicrobial agents, these efficient nano-drug delivery systems can target localized infections, ensure targeted delivery, enhance efficacy through increased drug penetration through physical barriers, and reduce systemic side effects for more effective treatment.
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Antibacterianos , Ciprofloxacina , Cobre , Polietilenglicoles , Staphylococcus aureus , Cobre/química , Cobre/farmacología , Polietilenglicoles/química , Antibacterianos/farmacología , Antibacterianos/química , Staphylococcus aureus/efectos de los fármacos , Animales , Ciprofloxacina/farmacología , Ciprofloxacina/química , Tecnología Química Verde , Pruebas de Sensibilidad Microbiana , Nanopartículas del Metal/química , Línea Celular , Infecciones Estafilocócicas/tratamiento farmacológico , Moringa oleifera/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Nanopartículas/química , CricetinaeRESUMEN
Staphylococcus aureus infections present a significant threat to the global healthcare system. The increasing resistance to existing antibiotics and their limited efficacy underscores the urgent need to identify new antibacterial agents with low toxicity to effectively combat various S. aureus infections. Hence, in this study, we have screened T-muurolol for possible interactions with several S. aureus-specific bacterial proteins to establish its potential as an alternative antibacterial agent. Based on its binding affinity and interactions with amino acids, T-muurolol was identified as a potential inhibitor of S. aureus lipase, dihydrofolate reductase, penicillin-binding protein 2a, D-Ala:D-Ala ligase, and ribosome protection proteins tetracycline resistance determinant (RPP TetM), which indicates its potentiality against S. aureus and its multi-drug-resistant strains. Also, T-muurolol exhibited good antioxidant and anti-inflammatory activity by showing strong binding interactions with flavin adenine dinucleotide (FAD)-dependent nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, and cyclooxygenase-2. Consequently, molecular dynamics (MD) simulation and recalculating binding free energies elucidated its binding interaction stability with targeted proteins. Furthermore, quantum chemical structure analysis based on density functional theory (DFT) depicted a higher energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital (EHOMO-LUMO) with a lower chemical potential index, and moderate electrophilicity suggests its chemical hardness and stability and less polarizability and reactivity. Additionally, pharmacological parameters based on ADMET, Lipinski's rules, and bioactivity score validated it as a promising drug candidate with high activity toward ion channel modulators, nuclear receptor ligands, and enzyme inhibitors. In conclusion, the current findings suggest T-muurolol as a promising alternative antibacterial agent that might be a potential phytochemical-based drug against S. aureus. This study also suggests further clinical research before human application.
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Antibacterianos , Descubrimiento de Drogas , Fitoquímicos , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/química , Staphylococcus aureus/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/química , Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Simulación por Computador , Humanos , Antioxidantes/farmacología , Antioxidantes/químicaRESUMEN
The isolation and identification of pathogenic bacteria from a variety of samples are critical for controlling bacterial infection-related health problems. The conventional methods, such as plate counting and polymerase chain reaction-based approaches, tend to be time-consuming and reliant on specific instruments, severely limiting the effective identification of these pathogens. In this study, we employed the specificity of the cell wall-binding (CBD) domain of the Staphylococcus aureus bacteriophage 80 alpha (80α) endolysin towards the host bacteria for isolation. Amidase 3-CBD conjugated magnetic beads successfully isolated as few as 1 × 102 CFU/mL of S. aureus cells from milk, blood, and saliva. The cell wall hydrolyzing activity of 80α endolysin promoted the genomic DNA extraction efficiency by 12.7 folds on average, compared to the commercial bacterial genomic DNA extraction kit. Then, recombinase polymerase amplification (RPA) was exploited to amplify the nuc gene of S. aureus from the extracted DNA at 37 °C for 30 min. The RPA product activated Cas12a endonuclease activity to cleave fluorescently labeled ssDNA probes. We then converted the generated signal into a fluorescent readout, detectable by either the naked eye or a portable, self-assembled instrument with ultrasensitivity. The entire procedure, from isolation to identification, can be completed within 2 h. The simplicity and sensitivity of the method developed in this study make it of great application value in S. aureus detection, especially in areas with limited resource supply.
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Técnicas Biosensibles , Endopeptidasas , Staphylococcus aureus , Staphylococcus aureus/aislamiento & purificación , Staphylococcus aureus/virología , Técnicas Biosensibles/métodos , Endopeptidasas/química , Endopeptidasas/aislamiento & purificación , Endopeptidasas/genética , Bacteriófagos/química , Bacteriófagos/genética , Bacteriófagos/aislamiento & purificación , Humanos , Fagos de Staphylococcus/genética , Fagos de Staphylococcus/química , Fagos de Staphylococcus/aislamiento & purificación , Animales , Técnicas de Amplificación de Ácido Nucleico/métodos , Infecciones Estafilocócicas/microbiología , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Nucleasa Microcócica/química , Nucleasa Microcócica/metabolismo , Nucleasa Microcócica/genética , Proteínas Virales/química , Proteínas Virales/metabolismoRESUMEN
The human body harbors a substantial population of bacteria, which may outnumber host cells. Thus, there are multiple interactions between both cell types. Given the common presence of Staphylococcus aureus in the human body and the role of Th17 cells in controlling this pathogen on mucous membranes, we sought to investigate the effect of α-hemolysin, which is produced by this bacterium, on differentiating Th17 cells. RNA sequencing analysis revealed that α-hemolysin influences the expression of signature genes for Th17 cells as well as genes involved in epigenetic regulation. We observed alterations in various histone marks and genome methylation levels via whole-genome bisulfite sequencing. Our findings underscore how bacterial proteins can significantly influence the transcriptome, epigenome, and phenotype of human Th17 cells, highlighting the intricate and complex nature of the interaction between immune cells and the microbiota.
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Toxinas Bacterianas , Epigénesis Genética , Proteínas Hemolisinas , Staphylococcus aureus , Células Th17 , Staphylococcus aureus/inmunología , Staphylococcus aureus/genética , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/inmunología , Proteínas Hemolisinas/metabolismo , Humanos , Células Th17/inmunología , Células Th17/metabolismo , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/genética , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Metilación de ADN , Diferenciación Celular , TranscriptomaRESUMEN
Introduction: Despite years of efforts to develop new antibiotics for eradicating multidrug-resistant (MDR) and multi-virulent Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Staphylococcus aureus (VRSA) infections, treatment failures and poor prognoses in most cases have been common. Therefore, there is an urgent need for new therapeutic approaches targeting virulence arrays. Our aim is to discover new anti-virulence therapies targeting MRSA and VRSA virulence arrays. Methodology: We employed phenotypic, molecular docking, and genetic studies to screen for anti-virulence activities among selected promising compounds: Coumarin, Simvastatin, and Ibuprofen. Results: We found that nearly all detected MRSA and VRSA strains exhibited MDR and multi-virulent profiles. The molecular docking results aligned with the phenotypic and genetic assessments of virulence production. Biofilm and hemolysin productions were inhibited, and all virulence genes were downregulated upon treatment with sub-minimum inhibitory concentration (sub-MIC) of these promising compounds. Ibuprofen was the most active compound, exhibiting the highest inhibition and downregulation of virulence gene products. Moreover, in vivo and histopathological studies confirmed these results. Interestingly, we observed a significant decrease in wound area and improvements in re-epithelialization and tissue organization in the Ibuprofen and antimicrobial treated group compared with the group treated with antimicrobial alone. These findings support the idea that a combination of Ibuprofen and antimicrobial drugs may offer a promising new therapy for MRSA and VRSA infections. Conclusion: We hope that our findings can be implemented in clinical practice to assist physicians in making the most suitable treatment decisions.