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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
BACKGROUND: The increasing prevalence of antibiotic-resistant bacterial infections has led to the search for new approaches. OBJECTIVE: This study aimed to evaluate the effects of carvacrol and N-acetyl cysteine, both individually and in combination, on the planktonic cells and biofilm formations of Staphylococcus aureus, including methicillin-resistant and methicillin-sensitive strains. Additionally, the study sought to perform cytotoxicity tests and chemical characterization to further understand the properties and potential applications of these substances. METHODS: A total of 19 S. aureus strains were included in the study. Minimum inhibitory concentration and minimum bactericidal concentration were determined by assays. Synergy analysis tests were carried out. Cytotoxicity tests were conducted on the fibroblast cell line. Characterization test was performed. RESULTS: While Minimum inhibitory concentration and minimum bactericidal concentration values for carvacrol varied between 250 and 500 µg/ml, these values were in the range of 32-64 mg/ml for N-acetyl cysteine. Biofilm formation activities were identified. A total of eight strains, including six clinical and two standard strains with the highest biofilm-forming ability, were selected for combination studies. The combination of Carvacrol and N-acetyl cysteine exhibited synergistic and partially synergistic effects on the tested planktonic and biofilm strains, and these effects were dose-dependent. Carvacrol was found to be the most active drug at the end of 24, 48, and 72 h. Regarding the synergistic effect of N-acetyl cysteine + carvacrol, it was revealed to exhibit higher activity than N-acetyl cysteine and lower activity than carvacrol. CONCLUSION: The combination of carvacrol and N-acetyl cysteine demonstrated synergistic and partially synergistic effects against both planktonic and biofilm forms of Staphylococcus aureus. These results suggest potential for novel approaches in managing orthopedic infections, warranting further research to explore their therapeutic applications.
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Staphylococcus aureus biofilm is a common bio-contaminant source that leads to food cross-contamination and foodborne disease outbreaks. Hence, there is a need for searching novel antibiofilm agents with potential anti-virulence properties to control S. aureus contamination and infections in food systems. In this study, the antibiofilm effects of lactobionic acid (LBA) against S. aureus and its influence on virulence were explored. The minimum inhibition concentration of LBA on S. aureus was 8 mg/mL. Viable count and crystal violet assays revealed that LBA inhibited and inactivated S. aureus biofilms. Microscopic observations further confirmed the antibiofilm activity of LBA on S. aureus that disrupted the biofilm architecture and inactivated the viable cells in biofilms. Moreover, LBA decreased the release of extracellular DNA (eDNA) and extracellular polysaccharide (EPS) in S. aureus biofilms. LBA suppressed biofilm formation by intervening metabolic activity and reduced virulence secretion by repressing the hemolytic activity of S. aureus. Furthermore, LBA altered the expressions of biofilm- and virulence-related genes in S. aureus, further confirming that LBA suppressed biofilm formation and reduced the virulence secretion of S. aureus. The results suggest that LBA might be useful in preventing and controlling biofilm formation and the virulence of S. aureus to ensure food safety.
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Bicarbonate and CO2 are essential substrates for carboxylation reactions in bacterial central metabolism. In Staphylococcus aureus, the bicarbonate transporter, MpsABC (membrane potential-generating system) is the only carbon concentrating system. An mpsABC deletion mutant can hardly grow in ambient air. In this study, we investigated the changes that occur in S. aureus when it suffers from CO2/bicarbonate deficiency. Electron microscopy revealed that ΔmpsABC has a twofold thicker cell wall thickness compared to the parent strain. The mutant was also substantially inert to cell lysis induced by lysostaphin and the non-ionic surfactant Triton X-100. Mass spectrometry analysis of muropeptides revealed the incorporation of alanine into the pentaglycine interpeptide bridge, which explains the mutant's lysostaphin resistance. Flow cytometry analysis of wall teichoic acid (WTA) glycosylation patterns revealed a significantly lower α-glycosylated and higher ß-glycosylated WTA, explaining the mutant's increased resistance towards Triton X-100. Comparative transcriptome analysis showed altered gene expression profiles. Autolysin-encoding genes such as sceD, a lytic transglycosylase encoding gene, were upregulated, like in vancomycin-intermediate S. aureus mutants (VISA). Genes related to cell wall-anchored proteins, secreted proteins, transporters, and toxins were downregulated. Overall, we demonstrate that bicarbonate deficiency is a stress response that causes changes in cell wall composition and global gene expression resulting in increased resilience to cell wall lytic enzymes and detergents.
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Bicarbonatos , Pared Celular , Staphylococcus aureus , Staphylococcus aureus/metabolismo , Staphylococcus aureus/genética , Bicarbonatos/metabolismo , Pared Celular/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Estrés Fisiológico , Regulación Bacteriana de la Expresión Génica , Dióxido de Carbono/metabolismoRESUMEN
The cell wall is an indispensable element of bacterial cells and a long-known target of many antibiotics. Penicillin, the first discovered beta-lactam antibiotic inhibiting the synthesis of cell walls, was successfully used to cure many bacterial infections. Unfortunately, pathogens eventually developed resistance to it. This started an arms race, and while novel beta-lactams, either natural or (semi)synthetic, were discovered, soon upon their application, bacteria were developing resistance. Currently, we are facing the threat of losing the race since more and more multidrug-resistant (MDR) pathogens are emerging. Therefore, there is an urgent need for developing novel approaches to combat MDR bacteria. The cell wall is a reasonable candidate for a target as it differentiates not only bacterial and human cells but also has a specific composition unique to various groups of bacteria. This ensures the safety and specificity of novel antibacterial agents that target this structure. Due to the shortage of low-molecular-weight candidates for novel antibiotics, attention was focused on peptides and proteins that possess antibacterial activity. Here, we describe proteinaceous agents of various origins that target bacterial cell wall, including bacteriocins and phage and bacterial lysins, as alternatives to classic antibiotic candidates for antimicrobial drugs. Moreover, advancements in protein chemistry and engineering currently allow for the production of stable, specific, and effective drugs. Finally, we introduce the concept of selective targeting of dangerous pathogens, exemplified by staphylococci, by agents specifically disrupting their cell walls.
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Antibacterianos , Pared Celular , Bacterias Grampositivas , Pared Celular/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Bacterias Grampositivas/efectos de los fármacos , Humanos , Bacteriocinas/farmacología , Bacteriocinas/química , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , BacteriófagosRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) is a highly threatening foodborne pathogen capable of causing severe organ and life-threatening diseases. Over the past years, various commercial antibiotics have been used to treat MRSA infections. However, these commercial antibiotics have not yielded efficient results and also cause other side effects; therefore, there is a need for the development of effective alternatives to replace these commercial antibiotics. Suberanilic acid, an amide alkaloid obtained from the endophytic fungus Pestalotiopsis trachycarpicola DCL44, has been identified as a significant antimicrobial agent. However, its antibiotic properties on multi-drug-resistant bacteria such as MRSA have not been fully explored. Therefore, to investigate the potential antimicrobial mechanism of suberanilic acid against MRSA, a quantitative proteomics approach using tandem mass tagging (TMT) was used. The results obtained in the study revealed that suberanilic acid targets multiple pathways in MRSA, including disruption of ribosome synthesis, inhibition of membrane translocation for nutrient uptake (ABC transporter system), and causing dysregulation of carbohydrate and amino acid energy metabolism. These results provide new insights into the mechanism of action of suberanilic acid against MRSA and offer technical support and a theoretical basis for the development of novel food antimicrobial agents derived from endophytic fungal origin.
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Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/farmacología , Antibacterianos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pestalotiopsis , Endófitos/química , Pruebas de Sensibilidad Microbiana , Proteómica/métodosRESUMEN
This study proposes an affordable plasma device that utilizes a parallel-plate dielectric barrier discharge geometry with a metallic mesh electrode, featuring a straightforward 3D-printed design. Powered by a high-voltage supply adapted from a cosmetic plasma device, it operates on atmospheric air, eliminating the need for gas flux. Surface modification of polyethylene treated with this device was characterized and showed that the elemental composition after 15 min of plasma treatment decreased the amount of C to ~80 at% due to the insertion of O (~15 at%). Tested against Candida albicans and Staphylococcus aureus, the device achieved a reduction of over 99% in microbial load with exposure times ranging from 1 to 10 min. Simultaneously, the Vero cell viability remained consistently high, namely between 91% and 96% across exposure times. These results highlight this device's potential for the surface modification of materials and various infection-related applications, boasting affordability and facilitating effective antimicrobial interventions.
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Candida albicans , Gases em Plasma , Staphylococcus aureus , Propiedades de Superficie , Candida albicans/efectos de los fármacos , Gases em Plasma/química , Gases em Plasma/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Células Vero , Chlorocebus aethiops , Viabilidad Microbiana/efectos de los fármacos , Polímeros/químicaRESUMEN
Myricetin (MYR) is a flavonoid with favorable biological activities. In this study, MYR oxidation products (MYRox) were generated through enzymatic oxidation of MYR using horseradish peroxidase. The results showed enzymatic oxidation enhanced the water solubility and antibacterial activity against Staphylococcus aureus (S. aureus) of MYR. Further experiments showed the antibacterial effects of MYRox were conferred by MYR organic phase oxidation products (MYRoo). Both MYR and MYRoo could disrupt the cell membrane integrity, bind to the genomic DNA, affect protein synthesis and degradation, and alter the ROS levels in S. aureus. However, they exerted these effects with different strengths and ways. Finally, MYR or MYRoo can be used as an inhibitor against S. aureus in the cabbage food system, with MYRoo having better effect. This study demonstrated that enzymatic oxidation is an effective approach to improve the water solubility and antibacterial activity of MYR, enhancing its potential application in food preservation.
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In recent times, there has been a notable surge in the investigation of new antibiotic substances derived from natural origins. Pleurotus eous is an edible mushroom that has various useful bioactive substances and therapeutic properties, including antimicrobial activity. The present study aims to evaluate the antimicrobial efficacy of the methanolic extract of P. eous (MEPE) through in vitro method. Notably, S. aureus demonstrated the highest susceptibility to MEPE, prompting further investigation into its antibacterial mechanisms via scanning electron microscopy (SEM), membrane integrity, and permeability assays. The in-vivo antibacterial effect of MEPE against S. aureus was also assessed, including analysis of bacterial burden in organs, hematological profiles, and cytokine profiles. Detailed phytochemical analyses of MEPE were conducted using GC-MS. Results revealed MEPE's significant (p < 0.05) efficacy against Gram-positive bacteria, particularly S. aureus (77.56 ± 0.4 µg/mL and 34 ± 6.9 µg/ml in turbidometric and viable cell count assays, respectively). Moreover, membrane permeability significantly increased in 60.32 % of S. aureus isolates following treatment with MEPE. Additionally, mice receiving MEPE exhibited decreased levels of TNF-α, IL-1ß, and IL-6, suggesting its potential in combating S. aureus infection in animal models.
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OBJECTIVES: Bacterial infections are a noteworthy global health concern that necessitates the development of new strategies to enhance the potency and efficacy of antibiotics. Rifaximin (RFX), a broad-spectrum antibiotic, exhibits promising antibacterial activity against several bacterial strains. However, its insolubility and impermeability impede the exploitation of its full potential. The objective of the current study is to overcome the inherent caveats of RFX to exploit its maximum potential. SIGNIFICANCE: The exploitation of the full potential of antibiotics is necessary for reduction in their dosage and to minimize antibiotic pollution. This is a preliminary study aiming for maximum utilization of RFX at the target site and reduction in its release in unmetabolized form. METHODS: Gelatin is a biopolymer that has gained significant attention for biomedical applications owing to its inherent biocompatibility and biodegradability. In this study, bovine gelatin nanoparticles (BGNPs) were fabricated by the self-assembly method for their application as a carrier of RFX to enhance its antibacterial activity. The study employs a comprehensive range of experimental techniques to characterize the fabricated BGNPs such as DLS, Zeta Potential, FT-IR, AFM, SEM-EDX, and UV-Vis spectrophotometry. RESULTS: The average size of the fabricated BGNPs was 100 nm with a zeta potential value of -15.3 mV. The loading of RFX on BGNPs rendered an increase in its size to 136 nm with a zeta potential value of -16 mV. In-vitro assays and microscopic analyses were conducted to compare the antibacterial efficacy of RFX and RFX@BGNPs. An excellent loading capacity followed by sustained release of RFX from RFX@BGNPs rendered a significant enhancement in its pharmaceutical efficacy. The release of RFX from RFX@BGNPs followed the Higuchi and Korsmeyer-Peppas models. The antibacterial efficacy of RFX against Staphylococcus aureus has doubled by delivery through RFX@BGNPs, assessed by inhibitory and biofilm inhibitory assays. The enhancement in the antibacterial efficiency was further endorsed by SEM and microscopic imaging of the control and treated bacterial colonies. CONCLUSION: The study demonstrates an enhancement in the antimicrobial efficacy of RFX by its delivery in the form of RFX@BGNPs to exploit its full potential for practical applications.
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The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus is associated with necrotizing infections. After binding to complement 5a receptor (C5aR/CD88) and CD45 it causes cytolysis in polymorphonuclear neutrophils (PMNs) as well as inflammasome activation in monocytes. The objective of this study was to test if (ant)agonists of C5aR and CD45 can attenuate the effect of PVL on PMNs and monocytes. We tested the effect of various concentrations of six C5aR (ant)agonists (avacopan, BM213, DF2593A, JPE-1375, PMX205 and W-54011) and one CD45 antagonist (NQ301) to attenuate the cytotoxic effect of PVL on human PMNs and monocytes in vitro. Shifts in the half-maximal effective concentration (EC50) of PVL to achieve a cytotoxic effect on PMNs and modulation of inflammatory cytokine response from monocytes were determined by flow cytometry and IL-1ß detection. Pre-treatment of PMNs with avacopan, PMX205 and W-54,011 resulted in 3.6- to 4.3-fold shifts in the EC50 for PVL and were able to suppress IL-1ß secretion by human monocytes in the presence of PVL. BM213, DF2593A and NQ301 were unable to change the susceptibility of PMNs towards PVL or reduce inflammasome activation in monocytes. Avacopan, PMX205 and W-54,011 showed protection against PVL-induced cytotoxicity and suppressed IL-1ß secretion by monocytes. Clinical studies are needed to prove whether these substances can be used therapeutically as repurposed drugs.
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Toxinas Bacterianas , Exotoxinas , Leucocidinas , Monocitos , Neutrófilos , Receptor de Anafilatoxina C5a , Staphylococcus aureus , Leucocidinas/metabolismo , Leucocidinas/antagonistas & inhibidores , Exotoxinas/metabolismo , Exotoxinas/farmacología , Exotoxinas/antagonistas & inhibidores , Humanos , Toxinas Bacterianas/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Monocitos/inmunología , Staphylococcus aureus/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Receptor de Anafilatoxina C5a/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Antibacterianos/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismoRESUMEN
The purpose of this study was to establish a porcine model of urinary tract infection (UTI) with gram-positive uropathogens. Ten female domestic pigs were experimentally inoculated with human UTI isolates of Enterococcus faecalis (n = 3), Staphylococcus saprophyticus (n = 3), or Staphylococcus aureus (n = 4) and followed with regular urine samples. Bladders and kidneys were aseptically removed at termination (5-7 days post infection) and assessed by gross pathology and bacterial enumeration. Enterococcus faecalis (n = 3 of 3) and S. aureus (n = 2 of 4) successfully colonized the pig bladders. Inoculation with S. saprophyticus never resulted in detectable bacteriuria. All infected pigs had cleared the infection spontaneously before termination. Surprisingly, three (of four) pigs inoculated with S. aureus led to spontaneous infection with opportunistic pathogens. Also, one pig colonized with E. faecalis resulted in spontaneous infection with E. coli. In conlusion, the pig supports experimental UTI with E. faecalis for up to 24 h but not prolonged infection. S. aureus and S. saprophyticus fails to cause UTI in pigs and other animals should be considered for studying these pathogens.
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Antibiotic resistance is a major global challenge requiring new treatments and a better understanding of the bacterial resistance mechanisms. In this study, we compared ampicillin-resistant (R-AMP) and gentamicin-resistant (R-GEN) Staphylococcus aureus strains with a sensitive strain (ATCC6538) using metabolomics. We identified 109 metabolites; 28 or 31 metabolites in R-AMP or R-GEN differed from those in ATCC6538. Moreover, R-AMP and R-GEN were enriched in five and four pathways, respectively. R-AMP showed significantly up-regulated amino acid metabolism and down-regulated energy metabolism, whereas R-GEN exhibited an overall decrease in metabolism, including carbohydrate, energy, and amino acid metabolism. Furthermore, the activities of the metabolism-related enzymes pyruvate dehydrogenase and TCA cycle dehydrogenases were inhibited in antibiotic-resistant bacteria. Significant decreases in NADH and ATP levels were also observed. In addition, the arginine biosynthesis pathway, which is related to nitric oxide (NO) production, was enriched in both antibiotic-resistant strains. Enhanced NO synthase activity in S. aureus promoted NO production, which further reduced reactive oxygen species, mediating the development of bacterial resistance to ampicillin and gentamicin. This study reveals that bacterial resistance affects metabolic profile, and changes in energy metabolism and arginine biosynthesis are important factors leading to drug resistance in S. aureus.
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A series of known diterpenoids from Isodon serra (Maxim.) Hara exhibited antibacterial activities against Staphylococcus aureus and even methicillin-resistant S. aureus (MRSA). Among these diterpenoids, hebeirubescensin K (7), effusanin E (8), and nodosin (9) showed the optimal minimum inhibitory concentration (MIC) values ranging from 3.12 to 6.25 µg/mL against tested MRSA strains, and they also inhibited bacterial proliferation, biofilm formation, and key gene expressions related to adhesion and virulence of MRSA. In vivo experiments also demonstrated the antibacterial abilities of 7-9 as topical drugs and promoted wound healing caused by a MSRA infection. It is the first time that the anti-S. aureus and MRSA activities of diterpenoids from I. serra has been systematically reported. These current findings provide insight into the anti-MRSA mechanism of diterpenoids from I. serra; indicating these compounds may be used as antimicrobial agents and contribute to the development as well as application of I. serra in phytomedicine for MRSA infections.
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Background: Dairy products are considered some important sources of various nutritional compounds; however, pathogenic bacterial growth is a critical destructive factor to these products leading to consumer health and system financial crises. Aim: The current study was carried out to identify if there is any presence of Staphylococcus aureus-related enterotoxin genes in cheese samples. Methods: The research included the collection of 35 samples. The samples passed through conventional cultivation processes and a PCR method to detect the presence of icaA, sea, hla, and fnbA enterotoxin genes in these samples. Results: The conventional identification revealed the growth of S. aureus from the cheese samples. The PCR findings recorded the presence of the icaA, sea, hla, and fnbA in 31 (88.5%), 27 (77%), 19 (54%), and 12 (34%), respectively, of cheese samples. The sequencing revealed close similarities with global isolates, which reached up to 98.5% of identity. Conclusion: The current results indicate the presence of enterotoxin genes of S. aureus in high rates in the dairy products examined, which reveals critical problems of food safety due to the possible presence of enterotoxins in consumer dairy products.
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Queso , Enterotoxinas , Staphylococcus aureus , Queso/microbiología , Enterotoxinas/genética , Staphylococcus aureus/genética , Staphylococcus aureus/aislamiento & purificación , Microbiología de Alimentos , Reacción en Cadena de la Polimerasa/veterinariaRESUMEN
Purpose: Biofilms significantly contribute to the persistence and antibiotic resistance of Staphylococcus aureus infections. However, the regulatory mechanisms governing biofilm formation of S. aureus remain not fully elucidated. This study aimed to investigate the function of the S. aureus lineage-specific two-component system, desKR, in biofilm regulation and pathogenicity. Methods: Bioinformatic analysis was conducted to assess the prevalence of desKR across various S. aureus lineages and to examine its structural features. The impact of desKR on S. aureus pathogenicity was evaluated using in vivo mouse models, including skin abscess, bloodstream infection, and nasal colonization models. Crystal violet staining and confocal laser scanning microscopy were utilized to examine the impact of desKR on S. aureus biofilm formation. Mechanistic insights into desKR-mediated biofilm regulation were investigated by quantifying polysaccharide intercellular adhesin (PIA) production, extracellular DNA (eDNA) release, autolysis assays, and RT-qPCR. Results: The prevalence of desKR varied among different S. aureus lineages, with notably low carriage rates in ST398 and ST59 lineages. Deletion of desKR in NCTC8325 strain resulted in decreased susceptibility to ß-lactam and glycopeptide antibiotics. Although desKR did not significantly affect acute pathogenicity, the ΔdesKR mutant exhibited significantly reduced nasal colonization and biofilm-forming ability. Overexpression of desKR in naturally desKR-lacking strains (ST398 and ST59) enhanced biofilm formation, suggesting a lineage-independent effect. Phenotypic assays further revealed that the ΔdesKR mutant showed reduced PIA production, decreased eDNA release, and lower autolysis rates. RT-qPCR indicated significant downregulation of icaA, icaD, icaB, and icaC genes, along with upregulation of icaR, whereas autolysis-related genes remained unchanged. Conclusion: The desKR two-component system positively regulates S. aureus biofilm formation in a lineage-independent manner, primarily by modulating PIA synthesis via the ica operon. These findings provide new insights into the molecular mechanisms of biofilm formation in S. aureus and highlight desKR as a potential target for therapeutic strategies aimed at combating biofilm-associated infections.
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A 63-year-old immunocompromised male with a history of renal transplant and stage III large B-cell non-Hodgkin lymphoma undergoing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy presented with fever and a disseminated pustular eruption. Initial laboratory values indicated septicemia. Differential diagnoses included Sweet's syndrome, septic emboli, and leukocytoclastic vasculitis. Punch biopsies and bacterial cultures confirmed disseminated methicillin-sensitive Staphylococcus aureus (MSSA) infection. Histopathology revealed intraepidermal vesiculopustules and bacterial cocci colonies in the superficial dermis, suggesting hematogenous spread. The patient's indwelling venous access port was identified as the infection source and removed. Treatment included antibiotics such as cefepime, vancomycin, fluconazole, and acyclovir, as well as filgrastim for neutropenia. Following port removal and a four-week course of ceftriaxone, the patient's condition improved. This case highlights the importance of clinicopathologic correlation in diagnosing and managing disseminated staphylococcal infections in immunocompromised patients. The rare presentation of vesiculopustular eruptions secondary to MSSA emphasizes the need for prompt identification and treatment to prevent severe complications. This report contributes to the limited literature on disseminated staphylococcal infections presenting as vesiculopustular eruptions in immunocompromised individuals.
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Complement C3 (C3) is usually deposited spontaneously on the surfaces of invading bacteria prior to internalization, but the impact of C3 coating on cellular responses is largely unknown. Staphylococcus aureus (S. aureus) is a facultative intracellular pathogen that subverts autophagy and replicates in both phagocytic and nonphagocytic cells. In the present study, we deposited C3 components on the surface of S. aureus by complement opsonization before cell infection and confirmed that C3-coatings remained on the surface of the bacteria after they have invaded the cells, suggesting S. aureus cannot escape or degrade C3 labeling. We found that the C3 deposition on S. aureus notably enhanced cellular autophagic responses, and distinguished these responses as xenophagy, in contrast to LC3-associated phagocytosis (LAP). Furthermore, this upregulation was due to the recruitment of and direct interaction with autophagy-related 16-like 1 (ATG16L1), thereby resulting in autophagy-dependent resistance to bacterial growth within cells. Interestingly, this autophagic effect occurred only after C3 activation by enzymatic cleavage because full-length C3 without cleavage of the complement cascade reaction, although capable of binding to ATG16L1, failed to promote autophagy. These findings demonstrate the biological function of intracellular C3 upon bacterial infection in enhancing autophagy against internalized S. aureus.
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Autofagia , Complemento C3 , Fagocitosis , Infecciones Estafilocócicas , Staphylococcus aureus , Staphylococcus aureus/inmunología , Staphylococcus aureus/fisiología , Complemento C3/metabolismo , Humanos , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Animales , Interacciones Huésped-Patógeno , Ratones , Opsonización , Activación de ComplementoRESUMEN
The widespread prevalence and dissemination of antibiotic-resistant bacteria, coupled with the diminishing supply of new antibiotics, emphasize the pressing necessity for the exploration of innovative antibacterial agents. Previously, we detailed the impact of the small-molecule compound CY-158-11 on S. aureus biofilm. By hindering adhesion and PIA-mediated biofilm formation, subinhibitory concentrations of CY-158-11 exhibit antibiofilm activity toward S. aureus. Here, we sought to elucidate the antibacterial activity and mode of action of this compound. Upon CY-158-11 treatment in culture, the inhibition of bacterial growth, coupled with MBC to MIC of >4, indicated that CY-158-11 exerted a bacteriostatic effect. Particularly, CY-158-11 showed strong antibacterial activity against a wide variety of S. aureus, including multidrug-resistant bacteria. We found that CY-158-11 promoted the permeability of cell membrane and propidium iodide absorption as well as caused the dissipation of membrane potential. The effect of CY-158-11 on the mammalian cytoplasmic membrane was measured using hemolytic and cytotoxicity assays, and the skin irritation and systemic toxicity of the drug were measured by injecting the compound into the skin and tail vein of mice. Moreover, CY-158-11 exhibited considerable efficacy in a subcutaneous abscess mouse model of S. aureus infection. In conclusion, CY-158-11 possesses antibacterial properties, including inhibition of bacterial growth, damage to cell membranes, and treatment of skin abscesses, which can be a promising therapeutic option for combating S. aureus. IMPORTANCE: The combination of the rising incidence of antibiotic resistance and the shrinking antibiotic pipeline has raised concern about the postantibiotic era. New antibacterial agents and targets are required to combat S. aureus-associated infections. In this study, we identified a maleimide-diselenide hybrid compound CY-158-11 exhibiting antibacterial activity against S. aureus in vitro and in vivo at relatively low concentrations. Furthermore, the investigation of its mode of action revealed that CY-158-11 can selectively perturb the cytoplasmic membrane of bacteria without harming mammalian cells or mouse organs. Thus, CY-158-11 is a compelling novel drug for development as a new therapy for S. aureus infections.
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A simple and efficient method for obtaining monospecies and binary Staphylococcus aureus and Staphylococcus epidermidis cultures in sodium alginate gel matrix mimicking the natural microenvironment of the nasal cavity was proposed. The cultures were used for studying the effect of norepinephrine on monospecies and binary communities of two types of bacteria, S. aureus (invasive strain) and S. epidermis (commensal strain). After 24-h incubation, S. aureus predominated in the binary community, but later it was replaced by S. epidermis. Norepinephrine at higher concentrations accelerated this process without principally changing it. The model can be used to develop more effective complex antimicrobial drugs.