The current situation with drug-resistant microbial pathogens is critical, dictating an acute need for novel efficient antibiotics. Herein, we report a new class of antibiotics named gromomycins with significant activity, especially against drug-resistant Gram-positive pathogens, including methicillin- and daptomycin-resistant Staphylococcus aureus. Gromomycins are pentacyclic triterpenes with a cyclic guanidino group forming the fifth six-membered ring. We have used transposon mutagenesis to identify the gromomycin biosynthetic gene cluster, since it could not be assigned by any available bioinformatics tools, highlighting its unique biosynthetic route. Using gene cluster engineering, feeding experiments, and LC-MS and NMR analyses we have proposed the biosynthetic pathway for gromomycins, which are the first bacterial triterpenes synthesized independently of the squalene pathway. They also exhibit a so far unprecedented cyclization route that utilizes a hexaprenylguanidine linear precursor. Leveraging our understanding of their biosynthesis, we have identified additional gromomycin producers, resulting in the isolation of novel bioactive derivatives.

Three novel azaphilone hybrids (1-3) with two types of structural units, along with four known compounds (4-7), were obtained from the marine sediment-derived fungus Aspergillus terreus PPS1. Asperbenzophilone A (1) features an unprecedented 6/6/6/6 ring system containing a hemiketal group. Butyropyranones I and II (2 and 3) are equipped with an azaphilone fragment preasperpyranone and a butyrolactone, which are connected through ether bonds. Comprehensive spectroscopic techniques, ECD calculations, and deduction of biosynthetic pathways were used to confirm the planar structures and absolute configurations of the new compounds. Compound 2 displayed significant anti-MRSA activity. Additionally, compound 2 exhibited moderate cytotoxic activity on human tumor cell lines 786-O, 5637, MCF-7, A-673, and 293T and medium inhibitory activity against the SARS-CoV-2 main protease (Mpro/3CLpro).

Acute lung injury (ALI) seriously threatens human health and is induced by multiple factors. When ALI occurs, lung lesions affect gas exchange and may trigger respiratory failure. Current clinical treatments are limited, and traditional drug delivery has drawbacks. Berberine, a natural drug with anti-inflammatory effects, has difficulty in effectively exerting its efficacy.

The study designed a nano-micelle. Hydrophobic berberine was encapsulated with diselenide bonds as the linker. Then, lung epithelial cell membranes were extracted to encapsulate and disguise the nano-micelle. These nanoparticles were injected intravenously. Thanks to the cell membrane's specificity, they could bind to lung tissue, achieving targeted lung delivery. In the inflamed area of acute lung injury, the significantly increased reactive oxygen species level was used to break the diselenide bonds, enabling precise berberine release at the lung injury site.

The nano-drug (MM-NPs) was successfully prepared, with the encapsulation efficiency of berberine in the micelles reaching 68.2%. In a ROS environment, the nano-micelles could quickly release over 80% of berberine. In inflammatory MLE-12 cells, MM-NPs responded well to ROS, and cellular inflammatory factor levels were significantly improved after treatment. In a lipopolysaccharide (LPS)-induced pneumonia mouse model, MM-NPs achieved lung targeting. Further studies showed that MM-NPs administration significantly alleviated LPS-induced lung injury in mice. Additionally, evaluation indicated MM-NPs had good in-vivo safety with no obvious adverse reactions.

This study successfully developed a novel delivery system, MM-NPs, overcoming berberine's low bioavailability problem in treating acute lung injury. The system has excellent physicochemical properties, biocompatibility, and metabolic safety. In vitro and animal experiments verified it can significantly enhance the therapeutic effect, offering new ideas and hopes for acute lung injury treatment. In the future, clinical trials can be advanced, and new lung targeting strategies explored for more therapeutic breakthroughs.

Methicillin-resistant Staphylococcus aureus (MRSA) is a devastating global health concern. Hypervirulent strains are on the rise, causing morbidities and mortalities worldwide. In tertiary care hospitals, critically ill patients, those undergoing invasive procedures, and pediatric and geriatric patients are at risk. It is not fully clear how strains adapt and specialize in humans and emerge despite the well-established commonality of the S. aureus genome from humans and animals. This study investigates the influence of age-, gender-, and source-specific profiles (clinical, intensive care unit (ICU vs. non-ICU)) on the evolution of hospital-associated (HA)-MRSA versus community-associated (CA)-MRSA lineages. A total of 253 non-duplicate S. aureus isolates were obtained from May 2023 to March 2025. The patients were stratified by age and gender in ICUs and non-ICUs. Standard microbiology methods and Clinical and Laboratory Standards Institute (CLSI) guidelines were used for identification and susceptibility testing, with cefoxitin and oxacillin disk diffusions and molecular diagnosis confirming MRSA. Mann-Whitney U and Chi-square tests assessed the demographic distributions, clinical specimen sources, and MRSA/methicillin-sensitive S. aureus (MSSA) prevalence. Of 253, 41.9% originated from ICUs (71% male; 29% female) and 58.1% from non-ICU wards (64% male; 36% female). In both settings, MRSA colonized the two extremes of age (10-29 and 70+) for males and females, with different mid-life peaks or declines by gender. However, the overall demographic distribution did not differ significantly between the ICU and non-ICU groups (p = 0.287). Respiratory specimens constituted 37% and had the highest MRSA rate (42%), followed by blood (24.5%) and wounds (10.3%). In contrast, MSSA dominated wounds (20.3%). Overall, 73.9% were resistant to cefoxitin and cefotaxime, whereas vancomycin, linezolid, daptomycin, and tigecycline remained highly effective. Younger non-ICU patients (10-29) had higher MSSA, whereas older ICU ones showed pronounced HA-MRSA profiles. By the virtue of methicillin resistance, all MRSA were classified as multidrug resistance. Thus, MRSA colonization of the two extremes of life mostly in ICU seniors and the dominance of invasive MSSA and CA-MRSA patterns in non-ICU youth imply early age- and gender-specific adaptations of the three lineages. MRSA colonizes both ICU and non-ICU populations at extremes of age and gender specifically. High β-lactam resistance underscores the importance of robust stewardship and age- and gender-specific targeting in screening. These findings also indicate host- and organ-specificity in the sequalae of MSSA, CA-MRSA, and HA-MRSA evolutionary dynamics, emphasizing the need for continued surveillance to mitigate MRSA transmission and optimize patient outcomes in tertiary care settings.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant global health challenge, particularly associated with serious infections such as bacteremia. Lipoglycopeptide antibiotics, including vancomycin, dalbavancin, and daptomycin, are critical in MRSA treatment. In this study, we analyzed two MRSA isolates (XF1 and XF2) from a bacteremia patient treated with vancomycin. Antimicrobial susceptibility testing revealed that XF1 was sensitive to vancomycin, dalbavancin, and daptomycin, whereas XF2 exhibited 8- to 16-fold higher minimum inhibitory concentrations for these antibiotics, alongside a 4- to 8-fold reduction in resistance to β-lactam antibiotics, demonstrating the "β-lactam seesaw effect". Whole-genome sequencing confirmed their isogenic nature (ST59-SCCmecIV-t172), identifying seven mutations in XF2, including those in walK (G223S), vraR (D88Y), clpX (P64L), and ltaS (L62P), as well as a frameshift mutation in mgt (S39fs), likely contributing to resistance. Transmission electron microscopy and autolysis assays demonstrated that XF2 had a thicker cell wall and a slower autolysis rate compared to XF1. Phenotypic analysis showed that XF2 exhibited reduced growth rate, diminished virulence, and enhanced biofilm formation compared to XF1. Gene expression analysis supported these findings, revealing significant alterations in pathways related to cell wall metabolism, autolysis, and virulence regulation. These adaptations highlight the genomic and phenotypic plasticity of MRSA under antibiotic pressure, enabling resistance and persistence. This study underscores the urgent need for enhanced surveillance and alternative therapeutic strategies, including exploiting the β-lactam seesaw effect, to combat lipoglycopeptide-nonsusceptible MRSA.

This study aimed to investigate the "seesaw effect" of daptomycin (DAP) and ceftobiprole (BPR) on DAP-resistant (DAP-R) methicillin-resistant Staphylococcus aureus (MRSA) isolates.

Broth microdilution minimum inhibitory concentrations (MICs) of DAP and BPR were tested for laboratory-derived and clinical DAP-R MRSA isolates to estimate the "seesaw effect." Time-kill curves for seven representative DAP-R isolates were obtained using DAP and BPR to validate their synergistic activity in vitro. Whole genome sequencing as well as deletion and complementation of the mprF gene were performed to investigate the mechanisms of the "seesaw effect."

The BPR MICs decreased by half-fold in DAP-R MRSA isolates. The synergistic effect of DAP and BPR against representative clinical and community-associated MRSA (CA-MRSA) isolates was demonstrated in time-kill analyses, showing that synergistic activity was preferred in CA-MRSA compared with hospital-associated MRSA. The mprF mutations were identified in isolates exhibiting the "seesaw effect." These mutations increased the DAP MIC while decreasing the BPR MIC.

The "seesaw effect" between DAP and BPR was prevalent among DAP-R MRSA isolates. This phenomenon was associated with the mprF mutations of MRSA.

The fast emergence of bacteria resistance has already threatened global health, and immediate action is required before the emergence of another global pandemic. Despite substantial progress in the chemical synthesis of novel antimicrobial compounds and advancements in understanding antimicrobial resistance, there has been only a handful of new antibiotics coming to the market. Structurally Nanoengineered Antimicrobial Peptide Polymers (SNAPP-stars) are a new class of antimicrobials. Here, we show that lipidation of lysine-valine 16-armed SNAPP-star, S16 (lipo-SNAPP-star) where the N-terminal arms are conjugated with different fatty acids (caproic, C6, lauric, C12, and stearic acid, C18) enhanced the antimicrobial activity toward S. aureus and MRSA. Lipidation enhanced activity by targeting the SNAPP-stars to the bacterial surface by binding to peptidoglycan, leading to greater inner membrane disruption and depolarization. Lipo-SNAPP-stars killed bacteria in under a minute, whereas vancomycin took >16 h. Lipo-SNAPP-stars were found to preferentially target and kill MRSA rather than S. aureus in a mixed bacteria model. Lipid chain length affected activity, with C6-S16 having greater activity compared to C12-S16 > C18-S16. Lauric and stearic acid enhanced SNAPP-star binding to the bacterial surface and membrane depolarization but impeded SNAPP-stars' ability to transit through the peptidoglycan layer to disrupt the inner membrane. Microbial flow cytometry showed that lipidation aided binding to bacteria via lipoteichoic acid and specifically to peptidoglycan. Further, lipid length enhanced bacterial binding with C18-S16 > C12-S16 > C6-S16 = S16, which contrasts the activity order of C6-S16 > S16 ≫ C12-S16 ≫ C18-S16. Our data demonstrate that lipidation enhances antimicrobial activity by targeting and binding an antimicrobial to peptidoglycan, but increasing lipid length reduces activity by retaining the antimicrobial in the outer layer. Lipidation of SNAPP-stars did not increase cytotoxicity, with C6-S16 having an improved therapeutic index compared to S16. Our data show how lipidation of SNAPP-stars enhances its antimicrobial activity, resulting in a highly biocompatible antimicrobial that targets and kills the "superbug" MRSA within minutes.

Methicillin resistant Staphylococcus aureus (MRSA) is a human pathogen that can cause hospital and community acquired infections. Biofilm formation is a major virulence factor contributing to its pathogenicity. This study aimed to detect biofilm formation ability among methicillin resistant Staphylococcus aureus (MRSA) clinical isolates and determine SCCmec types.

A total of 115 S. aureus were isolated from various clinical samples collected at Nepal Armed Police Hospital from August 2022 to February 2023. The antibiotic susceptibility test was performed via a modified Kirby Bauer disc diffusion method following CLSI guidelines. Phenotypic detection of biofilm formation was performed by microtiter plate assay. Polymerase chain reaction was performed to detect mecA, icaA and SCCmec types.

More than 90% of the isolates were resistant to cefixime and penicillin. Among the total isolates, 66% were multidrug resistant. The disc diffusion method detected 60% of the isolates as MRSA, with 15 isolates lacking the mecA gene. Different levels of biofilm biomass were observed among 86 (75%) of the isolates by microtiter plate method. PCR revealed the presence of the icaA gene in a low number of the isolates (16%). Compared with biofilm nonproducer isolates, biofilm producing S. aureus isolates presented a greater incidence of antibiotic resistance with multi drug resistance (MDR). SCCmec type V (21%) predominated, followed by type II (13%) and most of them were MDR and biofilm producers.

Our results indicate a relatively high incidence of community acquired S. aureus circulating in the hospital setting. This study is the first to explore the associations between SCCmec types and biofilm formation among clinical isolates in Nepal. Monitoring the prevalence of biofilm producing S. aureus provides valuable insights into the evolving epidemiology of healthcare associated infections, facilitating the development of targeted infection control strategies.

Bloodstream infections (BSIs) caused by Staphylococcus aureus are common worldwide, representing one of the most relevant issues in clinical infectious diseases practice. In particular, BSIs by methicillin-resistant S. aureus (MRSA-BSI) are still today a challenge since mortality burden remains elevated although decades of research.

The following topics regarding MRSA-BSI were reviewed and discussed by resorting to best available evidence retrieved from PubMed/MEDLINE up to October 2024: i) epidemiology; ii) microbiology; iii) classification, with a focus on complicated and not complicated forms; iv) the structured approach to the patient; v) pharmacokinetics and pharmacodynamics of the main antimicrobial options; vi) controversies regarding the best therapeutic approach.

Despite ongoing efforts to better stratify and manage MRSA-BSI, there is no universally accepted classification system accurately distinguishing between uncomplicated/low risk and complicated/high risk forms. Biomarkers such as interleukin(IL)-10 hold promise in order to enable a more precise stratification, premise for an appropriate treatment plan. There is a theoretical rationale for implementing a combination therapy including a beta-lactam agent upfront, especially for patients considered at higher risk of unfavorable outcomes, but further data are necessary, and the same applies to newer adjuvants. Novel microbiological techniques may help in guiding antimicrobial duration.

Acute lung injury (ALI) which is caused by Staphylococcus aureus (SA), is a serious lung disease that threatens human health. Although some current treatments are effective in alleviating ALI, they still have a significant mortality rate. At present, adipose-derived mesenchymal stem cells (ADSCs)-derived extracellular vesicles (EVs) have been investigated for the treatment of various diseases. Here, we examined the role of ADSCs-derived EVs in regulating apoptosis and inflammation during ALI.

We showed that ADSCs and ADSCs-derived EVs supplementation could improve lung injury, restore mitochondrial function, and inhibit inflammation and apoptosis in ALI mice. Furthermore, miR-320a was present in EVs derived from ADSCs, and it can be transferred into lung tissue. In vitro, Casitas B-lineage lymphoma (CBL) expression was inhibited by miR-320a mimics. Finally, we found that miR-320a alleviated mitochondrial damage, inflammation, and apoptosis via the CBL/AMPK/JNK pathway.

In conclusion, EVs from ADSCs could alleviate ALI via the CBL/AMPK signaling pathway. Therefore, the purpose of our study was to investigate the application of ADSC-derived EVs in mitigating ALI by modulating metabolic processes.

Methicillin-resistant Staphylococcus aureus is a serious problem in healthcare due to its lethal severe infections and resistance to most antimicrobial agents. The number of new approved antimicrobial agents is declining, and combined with the spread of drug-resistant bacteria, it is predicted that effective antimicrobial agents against multidrug-resistant bacteria will be exhausted. We conducted in silico and in vitro discovery of novel antimicrobial small molecules targeting the SaMurB enzyme involved in cell wall synthesis in Staphylococcus aureus (S. aureus). We performed hierarchical structure-based drug screenings to identify compounds and their analogues using a library of approximately 1.3 million compound structures. In vitro experiments with Staphylococcus epidermidis (S. epidermidis) identified three compounds (SH5, SHa6, and SHa13) that exhibit antibacterial activity. These three compounds do not have toxicity against human-derived cells. SHa13 exhibited remarkable activity (IC50 value =1.64 ± 0.01 µM). The active compound was predicted to bind to the active site of SaMurB by forming a hydrogen bond with Arg188 in both R and S bodies. These data provide a starting point for the development of novel cell wall synthesis inhibitors as antimicrobial agents targeting SaMurB.

Methicillin-resistant Staphylococcus aureus (MRSA) is a significant concern for skin and soft tissue infections. Apart from biofilm formation, these bacteria can reside intracellularly in phagocytic and nonphagocytic mammalian cells, complicating treatment with conventional antibiotics. Lipid-polymer hybrid nanoparticle (LPN) systems, combining the advantages of polymeric nanoparticles and liposomes, represent a new generation of nanocarriers with the potential to address these therapeutic challenges. In this study, gentamicin (Gen) and vancomycin (Van) were encapsulated in LPNs and evaluated for their ability to eliminate intracellular MRSA in phagocytic macrophage RAW-Blue cells and nonphagocytic epithelial HaCaT cells. Compared to free antibiotics at 100 μg/mL, LPN formulations significantly reduced intracellular bacterial loads in both cell lines. Specifically, LPN-Van resulted in approximately 0.7 Log CFU/well reduction in RAW-Blue cells and 0.3 Log CFU/well reduction in HaCaT cells. LPN-Gen showed a more pronounced reduction, with approximately 1.26 Log CFU/well reduction in RAW-Blue cells and 0.45 Log CFU/well reduction in HaCaT cells. In vivo, LPN-Van at 500 μg/mL significantly reduced MRSA biofilm viability compared to untreated controls (p < 0.001), achieving 98% eradication based on median values. In comparison, free vancomycin achieved a nonstatistically significant 79.2% reduction in biofilm viability compared to control. Prophylactically, LPN-Van at 500 μg/mL decreased MRSA levels to the limit of detection, resulting in a ∼3.5 Log reduction in the median CFU/wound compared to free vancomycin. No acute dermal toxicity was observed for LPN-Van based on histological analysis. These data indicate that LPNs show promise as a drug delivery platform technology to address intracellular infections.

Sepsis remains a leading cause of mortality in intensive care units (ICUs), with methicillin-resistant Staphylococcus aureus (MRSA) infections presenting significant treatment challenges. The impact of MRSA co-infection on sepsis outcomes necessitates further exploration.

We conducted a retrospective observational cohort study using the Medical Information Mart for Critical Care IV (MIMIC-IV-2.2) database. This cohort study included sepsis patients, scrutinizing baseline characteristics, MRSA co-infection, antimicrobial susceptibility, and their relations to mortality through Cox regression and Kaplan-Meier analyses.

Among 453 sepsis patients analyzed, significant baseline characteristic differences were observed between survivors (N = 324) and non-survivors (N = 129). Notably, non-survivors were older (70.52 ± 14.95 vs. 64.42 ± 16.05, P < 0.001), had higher lactate levels (2.82 ± 1.76 vs. 2.04 ± 1.56 mmol/L, P < 0.001), and higher SOFA scores (8.36 ± 4.18 vs. 6.26 ± 3.65, P < 0.001). Cox regression highlighted SOFA score (HR = 1.122, P = 0.003), body temperature (HR = 0.825, P = 0.048), and age (HR = 1.030, P = 0.004) as significant predictors of 28-day mortality. MRSA co-infection was found in 98.7% of cases without a significant effect on 28-day mortality (P = 0.9). However, sensitivity to cephalosporins, meropenem, and piperacillin/tazobactam was associated with reduced mortality. The area under the ROC curve for the combined model of age, SOFA, and body temperature was 0.73, indicating a moderate predictive value for 28-day mortality.

While MRSA co-infection's direct impact on 28-day sepsis mortality is minimal, antimicrobial sensitivity, especially to cephalosporins, meropenem, and piperacillin/tazobactam, plays a critical role in improving outcomes, underscoring the importance of antimicrobial stewardship and personalized treatment strategies in sepsis care.

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose serious treatment challenges, particularly in peritoneal dialysis patients due to their increased susceptibility to infections and antibiotic resistance. Vancomycin, a standard antibiotic treatment for MRSA, is currently being compromised due to the evolution of multidrug-resistant microorganisms. Therefore, there is an urgent need for alternative therapeutic strategies to obstruct the increasing antibiotic resistance and bacterial biofilm formation. The present study explores curcumin, a natural bioactive compound possessing antimicrobial and anti-inflammatory properties, as a potential therapeutic for MRSA. The standard optical density method confirmed the antibacterial activity of curcumin against Staphylococcus aureus (MTCC-3160). Furthermore, we investigated the impact of curcumin on bacterial metabolism. Metabolic analysis of S. aureus culture media over a 20-h period revealed that curcumin exerts bacteriostatic effects by inhibiting specific metabolic pathways, potentially linked to energy and sugar metabolism. Furthermore, the synergistic effect of curcumin combined with vancomycin was assessed against 20 clinical MRSA strains using the broth microdilution method. The results demonstrated that curcumin enhanced the antibacterial activity of vancomycin in 17 strains by reducing its minimum inhibitory concentration (MIC) significantly. The MIC of curcumin and vancomycin has been found to decrease significantly when used in combination, with curcumin's MIC decreased to as low as 0.5 µg/mL and vancomycin's MIC to 0.5 µg/mL for all strains. Synergistic effects were seen in 17 out of 20 strains, having fractional inhibitory concentration index values between 0.04 and 0.56. These findings suggest that curcumin-vancomycin combination therapy could offer an effective treatment strategy for MRSA infections which may combat antibiotic resistance and reduce treatment-related toxicity.

Staphylococcus aureus bacteremia (SAB) is a prevalent life-threatening infection often caused by methicillin-resistant S. aureus (MRSA). Up to 30% of SAB patients fail to clear infection even with gold-standard anti-MRSA antibiotics. This phenomenon is termed antibiotic-persistent MRSA bacteremia (APMB). The mechanisms driving APMB are complex and involve host phenotypes significantly impacting the immune response. Thus, defining early immune signatures and clinical phenotypes that differentiate APMB from antibiotic resolving (AR)MB could aid therapeutic success.

We assessed 38 circulating cytokines and chemokines using affinity proteomics in 74 matched pairs of vancomycin-treated SAB cases identified as ARMB or APMB after 5 days of blood culture.

Unsupervised hierarchical clustering segregated APMB from ARMB based on differential levels of IL-10, IL-12p40, IL-13, CCL4, and TGFα. Additionally, CXCL1, CCL22 and IL-17A significantly differed between APMB and ARMB when correlated with diabetes, dialysis, metastatic infection, or cardiac vegetation. Combining immune signatures with these relevant clinical phenotypes sharply increased accuracy of discriminating APMB outcome to 79.1% via logistic regression modeling. Finally, classification-regression tree analysis revealed explicit analyte thresholds associated with APMB outcome at presentation especially in patients with metastatic infection.

Collectively, this study identifies previously unrecognized cytokine and chemokine signatures that distinguish APMB and ARMB at presentation and in the context of host clinical characteristics associated with increased disease severity. Validation of a biomarker signature that accurately predicts outcomes could guide early therapeutic strategies and interventions to reduce risks of persistent SAB that are associated with worsened morbidity and mortality.

The prevalence of drug-resistant bacteria is a major challenge throughout the world, especially with respect to Gram-negative bacteria, such as drug-resistant Acinetobacter baumannii, which are regarded as the greatest bacterial threat to human health by the World Health Organization (WHO). In this work, 1,3,4-thiadiazole was introduced into the main skeleton of the classical peptidomimetic peptide deformylase (PDF) inhibitor in pursuit of highly efficient and broad-spectrum bacteriostatic drugs. Upon detailed structure-activity relationship study, PDF inhibitors that possess satisfactory activity against both Gram-positive and Gram-negative bacteria as well as a lower potential for methemoglobin toxicity were screened out. The mechanism of the empowered antibacterial activity against Gram-negative bacteria was also investigated. Finally, for the first time, remarkable protective efficacy against drug-resistant A. baumannii in a mouse model was achieved by a PDF inhibitor (compound 43). These findings can pave a way to new approaches to the development of novel broad-spectrum PDF inhibitors.

Multiple observational studies in methicillin-resistant Staphylococcus aureus and enterococcal infections have suggested that higher doses of daptomycin may be associated with better clinical outcomes. However, optimal daptomycin dosing in methicillin-sensitive S aureus bloodstream infections remains unclear. In this multicentered, retrospective, observational cohort study, we compared standard dose daptomycin (<8 mg/kg) vs high dose (≥8 mg/kg) for methicillin-sensitive S aureus bloodstream infections. In a propensity-weighted model, the composite outcome of treatment failure within 90 days was lower in the high-dose group relative to the standard dose group (odds ratio, 0.496; 95% CI, .306-.804). We did not detect any significant difference in safety outcomes.

Because of the urgent need for new antibiotics to treat drug-resistant bacterial pathogens, we employed an assay that rapidly screens large quantities of compounds for their ability to interfere with bacterial protein synthesis, in particular, the delivery of amino acids to the ribosome via tRNA and elongation factor Tu (EF-Tu). We have identified a drug lead, named MGC-10, which kills Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), with a MIC of 6 µM, while being harmless to mammalian cells in vitro in that concentration range. The antibacterial activity of MGC-10 was broad against over 50 strains of antibiotic-resistant samples obtained from hospital infections, where MGC-10 inhibited all tested strains of MRSA. Extensive selection and screening with MGC-10 did not yield any resistant strains, indicating it may have universal antibacterial activity against S. aureus. Pharmacokinetics performed in mice suggested that MGC-10 was too toxic for systemic use; however, it appears to have potential as a topical treatment for difficult-to-treat wounds or skin infections by Gram-positive pathogens such as MRSA. In a mouse skin-infection model with MRSA, MGC-10 performed as well or better than the present topical drug of choice, mupirocin. MGC-10 showed little, if any, accumulation in the livers of topically treated mice. These results bode well for the future use of MGC-10 in clinical application as it could be used to treat a broad range of S. aureus skin infections that are resistant to known antibiotics.IMPORTANCEThere is a critical need for new antibiotics to treat bacterial infections caused by pathogens resistant to many if not all currently available antibiotics. We describe here the identification of a prospective new antibiotic from high-throughput screening of a chemical library. The screening was designed to detect the inhibition of formation of a complex required for bacterial protein synthesis in all bacteria, the "ternary complex," comprised of elongation factor Tu (EF-Tu), aminoacyl-tRNA, and GTP. The inhibitory compound, renamed MGC-10, was effective against all Gram-positive bacteria, including a wide variety of methicillin-resistant Staphylococcus aureus (MRSA) strains. Although apparently too toxic for systemic use, the compound was safe and effective for topical use for treating skin infections in a mouse model. No resistance to the compound has been detected thus far, suggesting the potential to develop this compound for topical use to treat infections, especially those caused by pathogens resistant to existing antibiotics.

Skin flap transplantation is a conventional wound repair method in plastic and reconstructive surgery, but infection and ischemia are common complications. Photobiomodulation (PBM) therapy has shown promise for various medical problems, including wound repair processes, due to its capability to accelerate angiogenesis and relieve inflammation. This study investigated the effect of red and blue light on the survival of random skin flaps in methicillin-resistant Staphylococcus aureus (MRSA)-infected Sprague Dawley (SD) rats. Forty male SD rats were divided into control and light-emitting diode-red and blue light-treated (LED-RBL) groups at a ratio of 1:1 and a McFarland flap procedure was performed, which was subsequently infected with MRSA strains. After 7 days, the appearance and survival of the flaps were evaluated. The microvascular density was determined by hematoxylin and eosin (HE) staining. The expression levels of vascular endothelial growth factor (VEGF), hypoxia inducible factor 1α (HIF-1α), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (normally expressed as AKT) were detected by immunohistochemistry. The flap survival rate and microvascular density in the LED-RBL group were significantly higher than those in the control group (P < 0.05). In addition, the VEGF, HIF1-α, PI3K, and AKT levels were significantly higher in the LED-RBL group compared to the control group (P < 0.05). Red and blue light increased the survival area of the infected flap in rats by promoting angiogenesis, relieving oxidative stress, and reducing bacterial loads, indicating that PBM therapy is a convenient, simple, analgesic, and safe treatment intervention in promoting the survival rate of transplanted flaps after wound repair surgery.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) pose a significant challenge to global public health, characterized by high morbidity and mortality rates, particularly in immunocompromised patients. Despite extensive research, the rapid development of MRSA antibiotic resistance has outpaced current treatment methods, increasing the difficulty of treatment. Therefore, reviewing research on MRSA BSIs is crucial.

This study conducted a bibliometric analysis, retrieving and analyzing 1,621 publications related to MRSA BSIs from 2006 to 2024. The literature was sourced from the Web of Science Core Collection (WoSCC), and data visualization and trend analysis were performed using VOSviewer, CiteSpace, and Bibliometrix software packages.

The bibliometric analysis showed that research on MRSA BSIs was primarily concentrated in the United States, China, and Japan. The United States leads in research output and influence, with significant contributions from institutions such as the University of California system and the University of Texas system. The journal with the most publications is Antimicrobial Agents and Chemotherapy, while the most cited global publication is Vincent JL's article "Sepsis in European Intensive Care Units: Results of the SOAP Study" published in Critical Care Medicine in 2006. Cosgrove SE's article "Comparison of Mortality Associated with Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Meta-analysis" had the most co-citations. Key trends in the research include MRSA's antibiotic resistance mechanisms, the application of new diagnostic technologies, and the impact of COVID-19 on MRSA studies. Additionally, artificial intelligence (AI) and machine learning are increasingly applied in MRSA diagnosis and treatment, and phage therapy and vaccine development have become future research hotspots.

Methicillin-resistant Staphylococcus aureus BSIs remain a major global public health challenge, especially with the increasing severity of antibiotic resistance. Although progress has been made in new treatments and diagnostic technologies, further validation is required. Future research will rely on integrating genomics, AI, and machine learning to drive personalized treatment. Strengthening global cooperation, particularly in resource-limited countries, will be key to effectively addressing MRSA BSIs.

Staphylococcus aureus, a known contributor to non-healing wounds, releases vesicles (SAVs) that influence the delicate balance of host-pathogen interactions. Efferocytosis, a process by which macrophages clear apoptotic cells, plays a key role in successful wound healing. However, the precise impact of SAVs on wound repair and efferocytosis remains unknown.

Filtration, ultracentrifugation, and iodixanol density gradient centrifugation were used to purify the bacterial vesicles. Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB) were used to characterize the vesicles. Macrophage efferocytosis efficiency was assessed using flow cytometry and confocal microscopy, while efferocytosis at wound sites was analyzed through WB, FACS, and TUNEL staining. Hematoxylin and eosin (H&E) staining and wound size measurements were used to evaluate the wound healing process. Phosphorylation of signaling pathways was detected by WB, and efferocytosis receptor expression was measured using RNA sequencing, qPCR, and flow cytometry. siRNA and pathway inhibitors were used to investigate the roles of key receptors and signaling pathways in efferocytosis.

We identified SAVs at infected wound sites, linking them to delayed healing of wounds. SAVs inhibit efferocytosis by activating the TLR2-MyD88-p38 MAPK signaling pathway, which regulates efferocytosis receptor genes. This activation promoted cleavage and shedding of MerTK, a crucial receptor for macrophage-driven efferocytosis. Notably, selective inhibition of p38 MAPK prevented MerTK shedding, restored efferocytosis and accelerated wound healing significantly, offering a promising therapeutic approach for chronic, non-healing wounds.

These findings uncover a novel mechanism in S. aureus-infected wounds, highlighting how the disruption of efferocytosis via the TLR2-MyD88-p38 MAPK-MerTK axis becomes a key force behind impaired healing of wounds. Targeting this pathway could open up a new therapeutic avenue facilitating the treatment of chronic, non-healing skin injuries.

Methicillin-resistant Staphylococcus aureus (MRSA), a major cause of fatalities due to Antimicrobial Resistance (AMR), can act as an opportunistic pathogen despite being part of the normal human flora. MRSA infections, such as skin infections, pneumonia, sepsis, and surgical site infections, have risen significantly, with bloodstream infection cases increasing from 21% in 2016 to 35% in 2020. This surge has prompted research into alternative treatments like nanomaterials, photodynamic therapy, antimicrobial peptides (AMPs), and essential oils (EOs). AMPs and EOs have shown higher success rates compared to other alternatives, gaining significant attention for their effectiveness against MRSA. In this perspective, we have created a database for peptides and EOs that have been discovered to treat MRSA. Manual data curation was done to get related information on each of the anti-MRSA EOs and AMPs from the PubMed articles. This led to the curation of 1789 peptides (1029 unique) and 863 EOs (671 unique) that have been reported against MRSA. This was followed by database creation and the development of tools for sequence analysis and determination of physiochemical properties. This resource has been named 'The Anti-MRSA Resource' or 'TAMRSAR' which we believe will aid in future drug development efforts to combat the diseases caused by MRSA. The database is accessible on any web browser at the URL: https://bblserver.org.in/tamrsar/.

Staphylococcus aureus bloodstream infections pose a significant threat to public health and necessitate substantial healthcare resources. The optimal antimicrobial therapy for these infections remains a subject of debate. This systematic review and meta-analysis evaluated the efficacy and safety of early transition to oral antimicrobial therapy compared with continued intravenous (IV) therapy in patients with MRSA and MSSA bloodstream infections.

A PRISMA-guided systematic review and meta-analysis compared the early transition from intravenous to oral antibiotics with continued intravenous therapy in patients with S. aureus infections, utilizing relevant studies from the PubMed, Embase, Scopus, and Web of Science databases from August 2003 to June 2024.

This meta-analysis of 11 studies (N = 54-220, primarily male, age: mid-30s to early 70s) revealed a 71.6% higher risk of all-cause mortality for patients transitioned to early oral therapy than for those who continued IV therapy (RR: 1.716; 95% CI: 1.039-2.836; P = 0.035; I2 = 44%). Treatment failure, rehospitalization rates, adverse events, and hospital stay lengths did not differ significantly between groups.

Early oral antimicrobial therapy for S. aureus bloodstream infections significantly reduces mortality compared to prolonged intravenous treatment, without increasing the incidence of adverse events or the risk of rehospitalization, suggesting its safety and efficacy as an alternative therapeutic approach; however, further randomized controlled trials are necessary to corroborate these findings.

We share a case of a 38-year-old male with a history of hypertension and metabolic dysfunction-associated steatotic liver disease (MASLD) who was admitted for septic arthritis of the left sacroiliac joint, pyomyositis, and associated methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The patient presented with left hip pain, fever, tachycardia, and leukocytosis. A physical exam revealed left lateral hip tenderness and limited range of motion. Lumbar spine magnetic resonance imaging (MRI) revealed left sacroiliac septic arthritis, inflammation of multiple muscles consistent with pyomyositis, and a presacral abscess. Blood cultures and ​polymerase chain reaction results confirmed MSSA bacteremia, though no common predisposing risk factors were identified. The abscess was aspirated and the patient was treated with oxacillin and cefazolin. He showed clinical improvement with stable leukocytosis and was discharged on cefazolin via a peripherally inserted central catheter. Follow-up included a referral to rheumatology and a repeat of lumbar spine MRI. This case underscores the challenges in diagnosing MSSA bacteremia, especially in the absence of typical risk factors, and emphasizes the critical role of clinical suspicion and appropriate treatment strategies.

Bacteremia is a leading cause of morbidity and mortality worldwide. Rising prevalence and antimicrobial resistance (AMR) are critical public health issues. This study aims to determine the prevalence of bacteremia and the AMR pattern among patients in South Lebanon.

A cross-sectional study analyzed 76 positive blood cultures from Hammoud and Labib Hospitals in South Lebanon between September 2023 and March 2024. The phenotype and antimicrobial susceptibility of gram-positive and gram-negative were determined by using disk diffusion. Genotypically, polymerase chain reaction was used to detect the carbapenemase-resistant Enterobacterales (CRE), extended-spectrum β-lactamases (ESBL), and methicillin-resistant Staphylococcus aureus genes.

Out of 76 isolates, 38 (50%) were gram-positive and 38 (50%) were gram-negative. Escherichia coli was the most common among gram-negative (18. 42%), with 10.52% ESBL and 3.94% CRE. Staphylococcus coagulase negative was the most common among gram-positive (40.78%), followed by Staphylococcus aureus (6.57%), with 3.94% methicillin-resistant S. aureus. The prevalent ESBL gene was CTX-M (100%), and for the CRE, NDM (66.66%) was the most common gene. Regarding S. aureus, 66.66% were mecA.

The diverse bacteremia isolates and resistance genes in South Lebanon reflect global variability in incidence and resistance profiles.

High rates of bacteremia and AMR in South Lebanon underscore the need for effective antibiotic stewardship programs.

The misuse and abuse of antibiotics have led to the increase of drug resistance and the emergence of multi-drug resistant bacteria. Therefore, it is an urgent need to develop novel antimicrobial agents to address this problem. Natural products (NPs) could provide an effective strategy for the discovery of drug due to their wide range of source and biological activities. Ursolic acid (UA) is a naturally occurring compound known for its wide range of biological properties. In this study, a series of UA derivatives were rationally designed and synthesized by incorporating antibacterial potential fragments of benzenesulfonamide and indole, with the aim of obtaining novel UA derivatives for the treatment of bacterial infections. Based on the preliminary screening, UA derivatives 27 (yield of 26 %), containing 4-chlorobenzenesulfonamide and 6-carboxyindole pharmacophores, as well as 34 (yield of 42 %), containing 4-carboxybenzenesulfonamide and unsubstituted indole pharmacophores, were identified as promising antibacterial agents against Staphylococcus aureus, especially for methicillin-resistant Staphylococcus aureus (MRSA), possessing MICs of 1 μM. Furthermore, both of them also displayed low hemolytic activity, non-resistance, and low-toxicity to mammalian cells. In addition, further mechanistic studies revealed that 27 and 34 were able to inhibit and eliminate MRSA biofilm formation, affecting the permeability of bacterial cell membrane, leading to increase intracellular reactive oxygen species (ROS) and ultimately inducing bacterial death. Notably, 27 and 34 also showed promising in vivo efficacy against MRSA in a mouse wound model. These results suggested that 27 and 34 should have promising applications against MRSA infection.

Fermented foods, particularly fermented dairy products, offer significant health benefits but also present serious concerns. Probiotic bacteria, such as lactic acid bacteria (LAB), found in these foods have been strongly linked to the selection and dissemination of antibiotic resistance genes (ARGs). This study aims to examine the potential risks associated with fermented foods, despite their importance in human nutrition, by analyzing the entire production chain from raw material acquisition to storage. Focusing on cheese production as a key fermented food, the study will investigate various aspects, including dairy farm management, milk acquisition, milk handling, and the application of good manufacturing practices (GMP) and good hygiene practices (GHP) in cheese production. The findings of this review highlight that ARGs found in LAB are similar to those observed in hygiene indicator bacteria like E. coli and pathogens like S. aureus. The deliberate use of antibiotics in dairy farms and the incorrect use of disinfectants in cheese factories contribute to the prevalence of antibiotic-resistant bacteria in cheeses. Cheese factories, with their high frequency of horizontal gene transfer, are environments where the microbiological diversity of raw milk can enhance ARG transfer. The interaction between the raw milk microbiota and other environmental microbiotas, facilitated by cross-contamination, increases metabolic communication between bacteria, further promoting ARG transfer. Understanding these bacterial and ARG interactions is crucial to ensure food safety for consumers.

With the growing antibiotic resistance in Staphylococcus aureus, it is imperative to develop innovative therapeutic strategies against new targets to reduce selective survival pressures and incidence of resistance. In S. aureus, interbacterial communication relies on a quorum sensing system that regulates gene expression and physiological activities. Here, we identified that Visomitin, an antioxidant small molecule, exhibited bactericidal efficacy against methicillin-resistant S. aureus and its high tolerance phenotypes like intracellular bacteria and persister cells without inducing resistance. Critically, sub-minimal inhibitory concentrations (sub-MICs) of Visomitin could serve as a potent quorum-quencher reducing virulence production (such as haemolysin and staphyloxanthin), along with inhibiting biofilm formation, self-aggregation, and colony spreading of S. aureus. These effects were probably mediated by interfering with the S. aureus accessory gene regulator quorum sensing system. In summary, our findings suggest that Visomitin shows dual antimicrobial effects, including bactericidal effects at the concentrations above MIC and quorum sensing inhibition effects at sub-MICs, which holds promise for treating MRSA-related refractory infections.

The role of nociceptive nerves in modulating immune responses to harmful stimuli via pain or itch induction remains controversial. Compared to conventional surgery, various implant surgeries are more prone to infections even with low bacterial loads. In this study, an optogenetic technique is introduced for selectively activating peripheral nociceptive nerves using a fully implantable, wirelessly rechargeable optogenetic device. By targeting nociceptors in the limbs of awake, freely moving mice, it is found that activation induces anticipatory immunity in the innervated territory and enhances the adhesion of various host cells to the implant surface. This effect mediates acute immune cell-mediated killing of Staphylococcus aureus on implants and enables the host to win "implant surface competition" against Staphylococcus aureus. This finding provides new strategies for preventing and treating implant-associated infections.

Infections and antimicrobial resistance are becoming serious global public health crises. Multidrug-resistant Staphylococcus aureus (S. aureus) infections necessitate novel antimicrobial development. In this study, we demonstrated TAK-285, a novel dual HER2/EGFR inhibitor, exerted antibacterial activity against 17 clinical methicillin-resistant S. aureus (MRSA) and 15 methicillin sensitive S. aureus (MSSA) isolates in vitro, with a minimum inhibitory concentration (MIC) of 13.7 μg/mL. At 1 × MIC, TAK-285 completely inhibited the growth of S. aureus bacterial planktonic cells, and at 2 × MIC, it exhibited a superior inhibitory effect on intracellular S. aureus SA113-GFP compared to linezolid. Moreover, TAK-285 effectively inhibited biofilm formation at sub-MIC, eradicated mature biofilm and eliminated bacteria within biofilms, as confirmed by CLSM. Furthermore, the disruption of cell membrane permeability and potential was found by TAK-285 on S. aureus, suggesting its targeting of cell membrane integrity. Global proteomic analysis demonstrated that TAK-285 disturbed the metabolic processes of S. aureus, interfered with biofilm-related gene expression, and disrupted membrane-associated proteins. Conclusively, we repurposed TAK-285 as an antimicrobial with anti-biofilm properties against S. aureus by targeting cell membrane. This study provided strong evidence for the potential of TAK-285 as a promising antimicrobial agent against S. aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen that causes various diseases. Extensive researches highlight the significant role of gut microbiota and its metabolites, particularly spermidine, in infectious diseases. However, the immunomodulatory mechanisms of spermidine in MRSA-induced bloodstream infection remain unclear. Here, we confirmed the protective effects of spermidine in bloodstream infection in mice. Spermidine reduced the bacterial load and expression of inflammatory factors by shifting the macrophage phenotype to an anti-inflammatory phenotype, ultimately prolonging the survival of the infected mice. The protective effect against MRSA infection may rely on the elevated expression of protein tyrosine phosphatase nonreceptor 2 (PTPN2). Collectively, these findings confirm the immunoprotective effects of spermidine via binding to PTPN2 in MRSA bloodstream infection, providing new ideas for the treatment of related infectious diseases.

Staphylococcus aureus is a major cause of hospital-associated infections worldwide. The organism's ability to form biofilms has led to resistance against current treatment options such as beta-lactams, glycopeptides, and daptomycin. The ArlRS two-component system is a crucial regulatory system necessary for S. aureus autolysis, biofilm formation, capsule synthesis, and virulence. This study aims to investigate the role of the arlR deletion mutant in the detection and activation of S. aureus. We created an arlR deleted mutant and complementary strains and characterized their impact on the strains using partial growth measurement. The quantitative real-time PCR was performed to determine the expression of icaA, and the microscopic images of adherent cells were captured at the optical density of 600 to determine the primary bacterial adhesion. The biofilm formation assay was utilized to investigate the number of adherent cells using crystal violet staining. Eventually, the Triton X-100 autolysis assay was used to determine the influence of arlR on the cell autolytic activities. Our findings indicate that the deletion of arlR reduced the transcriptional expression of icaA but not icaR in the ica operon, leading to decrease in polysaccharide intercellular adhesin (PIA) synthesis. Compared to the wild-type and the complementary mutants, the arlR mutant exhibited decreased in biofilm production but increased autolysis. It concluded that the S. aureus response regulatory ArlR influences biofilm formation, agglutination, and autolysis. This work has significantly expanded our knowledge of the ArlRS two-component regulatory system and could aid in the development of novel antimicrobial strategies against S. aureus.

Staphylococcus aureus poses a significant threat as an opportunistic pathogen in humans, and animal medicine, particularly in the context of hospital-acquired infections (HAIs). Effective treatment is a significant challenge, contributing substantially to the global health burden. While antibiotic therapy remains the primary approach for staphylococcal infections, its efficacy is often compromised by the emergence of resistant strains and biofilm formation. The anticipated solution is the discovery and development of new antibacterial agents. However, this is a time consuming and expensive process with limited success rates. One potential alternative for addressing this challenge is the repurposing of existing antibiotics. This study investigated the potential of rifabutin (RFB) as a repurposed antibiotic for treating S. aureus infections. The minimum inhibitory concentration (MIC) of rifabutin was assessed by the broth microdilution method, in parallel to vancomycin, against 114 clinical isolates in planktonic form. The minimum biofilm inhibitory concentration (MBIC50) was determined by an adaptation of the broth microdilution method, followed by MTT assay, against a subset of selected 40 clinical isolates organized in biofilms. The study demonstrated that RFB MIC ranged from 0.002 to 6.250 μg/mL with a MIC50 of 0.013 μg/mL. RFB also demonstrated high anti-biofilm activity in the subset of 40 clinical isolates, with confirmed biofilm formation, with no significant MBIC50 differences observed between the MSSA and MRSA strains, in contrast to that observed for the VAN. These results highlight the promising efficacy of RFB against staphylococcal clinical isolates with different resistance patterns, whether in planktonic and biofilm forms.

The phytochemicals in the aerial parts of Euphorbia paralias (also known as Sea Spurge) and their anti-inflammatory and antimicrobial activities were investigated.

The methanolic extract was characterized using GC-MS and HPLC techniques. The anti-inflammatory feature was estimated through a Human Red Blood Cell (HRBC) membrane stabilization technique, while the antimicrobial feature was evaluated by the disc diffusion agar technique, minimum bactericidal concentration, and minimum inhibitory concentration (MIC) via micro-broth dilution method.

The GC/MS results demonstrated the existence of various phytochemicals, such as n-hexadecenoic acid, cis-11-eicosenoic acid, and methyl stearate, recognized for their anti-inflammatory and antibacterial features. The similarity of the phytochemical composition with other Euphorbia species emphasizes the genus-wide similarity. The anti-inflammatory activity exhibited a noteworthy inhibitory effect comparable to the reference drug indomethacin. The extract's antimicrobial potential was tested against a range of microorganisms, demonstrating significant action against Gram-positive bacteria and Candida albicans. The quantification of total phenolics and flavonoids further supported the therapeutic potential of the extract.

The methanolic extract from E. paralias emerges as a successful natural source of important active constituents with potential applications as anti-inflammatory and antimicrobial agents. This research provides a first step to valorize Euphorbia paralias insights as a source of worthwhile phytochemicals that have potential applications in the pharmaceutical industry.