ACS Infectious Diseases最新文献

Infections induced by methicillin-resistant Staphylococcus aureus (MRSA) are serious, highlighting the urgent need for exploring new antibacterial agents. Here, we report a new β-carboline derivative, termed ZLWH-67, that displays potent antibacterial activity against MRSA. ZLWH-67 exhibited bactericidal properties, low cytotoxicity and hemolytic toxicity, and good safety in vivo and was not susceptible to resistance. The potential antibacterial mechanisms of ZLWH-67 were studied by RNA-seq analysis and verified by RT-PCR. The results indicated that ZLWH-67 might exert its effects through multiple mechanisms, including biofilm formation suppression, membrane integrity disruption, energy metabolism disturbance, oxidative stress, and DNA damage. Further mechanistic studies demonstrated that ZLWH-67 potently inhibited biofilm formation and disrupted the integrity of the cell membrane. The disruption resulted in cytoplasmic DNA leakage, increased intracellular ROS, and inhibition of DNA synthesis, ultimately accelerating bacterial death. Notably, ZLWH-67 showed anti-MRSA efficacy in mouse skin and pneumonia infection models, comparable to vancomycin, emphasizing the potential as a promising anti-MRSA candidate.

Neurosyphilis sharespathological features with neurodegenerative diseases, notably amyloid-β(Aβ) deposition. Given this association, we sought to elucidate how Treponemapallidum (Tp) mediates Aβ pathology by examining its effects onboth Aβ production and clearance using the integrated invivorabbit model and in vitro systems.Rabbits subjected to intracisternal Tp for two months exhibited elevatedAβ levels in the hippocampus relative to PBS controls. Focusing on the highlyamyloidogenic Aβ_1-42 variant, we found that Tpexposure increased Aβ_1-42secretion in iPSC-derived neurons byupregulating theexpression of β-site amyloid precursor proteincleaving enzyme 1 without altering amyloid precursor protein levels.Concurrently, impairedmicroglial function in HMC3 cells, markedly inhibiting both phagocytosis anddegradationof Aβ_1-42, is quantified by flow cytometry and immunofluorescence. Mechanistic studies revealed that Tpactivates the TLR2/PI3K/AKT signaling pathway, which in turn impairedmicroglial Aβ uptake and clearance, a conclusion robustly supported by our finding thatpharmacological inhibition of this pathway restores clearance function.Our results establish adual mechanism whereby Tp promotes Aβ_1-42 accumulation throughcoordinated enhancement of neuronal production and impairment of microglialclearance, an effect mediated via TLR2/PI3K/AKT activation, providing a crucialmechanistic insight into neurosyphilis-associated neurodegeneration.

Microbial communities, or microbiota, are fundamental regulators of host immunity and infection outcomes across diverse body sites, including the gut, skin, respiratory tract, and vagina. Despite advances, infectious diseases remain a global challenge, exacerbated by antimicrobial resistance and emerging pathogens. This review explores the dynamic interplay between microbiota, host immune responses, and pathogens, highlighting how microbial interactions shape immune homeostasis and colonisation resistance. The review discusses therapeutic approaches leveraging probiotics, prebiotics, defined microbial consortia, and fecal microbiota transplantation to enhance resistance against bacterial, viral, fungal, and parasitic infections. These microbiome-based strategies represent promising, sustainable alternatives to conventional antibiotics, offering scalable and mechanism-driven interventions. This review further underscores the potential of microbiota-informed therapies to contribute to effective infectious disease prevention and management while addressing global health challenges.

Although Marburg and Měnglà viruses occupy different geographies and genera of the family Filoviridae, genetic and host similarities suggest spillover potential for the latter. While Marburg virus causes transmissible and often fatal hemorrhagic fever in humans, the pathogenicity of Měnglà virus is unknown. Understanding antibody cross-reactivity between the two viruses appears prudent in preparation for detecting the new virus and facilitating component-based studies of replication. Previously, while nanobodies to the monomeric nucleoprotein C-terminal domain (NPCTD) of Marburg virus recognized Měnglà virus NPCTD, cross-reactivity was too weak to quantify monovalent equilibrium concentrations. Here, using oligomeric NP in a nanobody-driven sandwich assay, the cross-reactivity deficit was essentially negated, suggesting we would be able to detect both viruses equally. Curious as to why monovalent reactivity was so disparate, we crystallized the Měnglà virus NPCTD-nanobody complex for X-ray crystal structure determination. Comparative analysis of the antibody–antigen interfaces revealed bonded and nonbonded opportunities at one location in the Marburg complex that were absent in the Měnglà complex. Mutagenesis of the NPCTDs, to make Marburg more Měnglà-like (H690N) and Měnglà more Marburg-like (N692H), resulted in dramatic ablation and restoration of nanobody binding, respectively, via changes in off-rates. Similar trends were observed for the more recently discovered Dehong virus, and dimeric enzymatic and fluorescent reporter fusions improved NP recognition potency within blotting and cell probing assays. Understanding the structural basis for cross-reactivity helps predict the likelihood of detecting viral variants based upon genomic sequence information and can inform the design of antibodies with broader recognition potential.

Candida (Candidozyma) auris is a multidrug-resistant fungal pathogen that presents a growing global health concern due to its resistance to conventional antifungals. This study evaluated the antifungal potential of zinc pyrithione (ZnPT) and nystatin (NYS), both individually and in combination, against C. auris. Minimum inhibitory and fungicidal concentrations were determined, alongside assays for biofilm inhibition and eradication, including tests on porcine skin. Mechanistic evaluations included assessments of cell membrane integrity, efflux pump inhibition, and sorbitol protection. Safety was analyzed through hemocompatibility, the Ames test, and acute toxicity in Tenebrio molitor larvae. ZnPT + NYS combination had a synergistic antifungal effect, effectively inhibiting biofilm formation and increasing membrane permeability, as evidenced by protein leakage. No nucleotide leakage or mutagenic effects were observed, indicating low genotoxic risk. While ZnPT alone exhibited toxicity in T. molitor, the combination remained within safe limits. Overall, the ZnPT + NYS combination demonstrated strong antifungal and antibiofilm activity against C. auris, with favorable safety outcomes. These findings support further investigation into its clinical potential as a treatment strategy against this emerging pathogen.

Ceftazidime (CAZ) is a critically important broad-spectrum antibiotic that is widely used in clinical practice. However, the rapid emergence of bacterial resistance to CAZ poses a significant challenge in treating infections caused by multidrug-resistant pathogens. In this study, we employed a metabolism-reprogramming approach to characterize key features of laboratory-evolved CAZ-resistant Escherichia coli K12 and identified repressed glutamate metabolism as a reprogrammable target. Exogenous glutamate effectively resensitized both lab-evolved and clinically isolated multidrug-resistant E. coli strains to CAZ. The resensitization mechanism operates through two synergistic pathways driven by glutamate metabolic flux. First, glutamate conversion to inosine activates the inosine-CpxA/CpxR-OmpF regulatory axis, increasing outer membrane permeability. Second, glutamate entry into the pyruvate cycle restores the proton motive force (PMF), energizing the inner membrane. Together, increased outer membrane permeability and a restored PMF synergistically enhance intracellular accumulation of CAZ─by facilitating its entry through the widened OmpF porin and promoting its active uptake across the cytoplasmic membrane. This dual-mechanism strategy provides a novel two-pronged approach to overcoming CAZ resistance. Our findings underscore the potential of targeting bacterial metabolic pathways to restore susceptibility and extend the utility of existing antibiotics against resistant pathogens.

The surge of infections accompanied by a limited supply of potent antibacterial agents has resulted in an emerging need for broad-spectrum treatments. The ability of superbugs to form resilient biofilms exacerbates the situation. Although natural polymers such as chitosan and its derivatives have been studied for their biocompatibility and antibacterial activity, quaternization and thiolation have been explored separately as distinct modification strategies to enhance their functional performance. However, the synergistic effects of integrating the complementary properties of quaternization and thiolation in the same polymer have not been explored. In this respect, we synthesized quaternary thiolated polymer (QTP) by reacting N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) with thioglycolic acid. QTP shows broad-spectrum activity against drug-resistant Gram-positive and Gram-negative bacteria. The polymer exhibits antioxidant properties that mitigate hyperinflammation while having low in vitro and in vivo toxicity. QTP achieves a significantly reduced bacterial biofilm (>99.9%). When assessed in a superficial wound infection murine model, the polymer not only completely eradicates MRSA burden in vivo but also aids in restoring normal dermal architecture. These findings position QTP as a promising therapeutic candidate for countering resistant bacterial infections.

Flow cytometry is an essential tool to discern phenotypic and functional differences in single cell mixtures. Most efforts to develop and deploy multicolor flow panels have focused on mammalian cells, whereas a more limited palette of tools exists for microbiota and pathogen-focused analyses. Here, we describe a systematic screen of commercially available nucleic acid dyes to aid in the development of multicolor panels for both Gram-negative and Gram-positive bacteria. We found that dyes show responses that varied by orders of magnitude across two model bacteria. When examining whether dyes can help to discriminate intact cells from noncellular debris, we discovered that certain compounds also bind to purified peptidoglycan with intensities comparable to those observed with bacterial binding. Together, these data will aid in the selection of specific reagents to use in the development of larger scale, multicolor panels for microbial flow cytometry.

As a leading cause of healthcare-associated infections, catheter-associated urinary tract infections (CAUTIs) present a unique challenge due to the high prevalence of multidrug-resistant and polymicrobial pathogens. Distinct from uncomplicated UTIs, the insertion of a urinary catheter provokes tissue damage that triggers inflammation, plasma extravasation, and the deposition of host fibrinogen. This inflammatory response drives the robust recruitment of immune cells and plasma extravasation, leading to the accumulation of fibrinogen─a key coagulation protein─on the device and bladder epithelium. This fibrinogen-rich environment creates a unique niche for intricate host–pathogen interactions. Crucially, uropathogens exploit these deposits to establish persistent biofilms, while the protein scaffold simultaneously modulates host immunity. Understanding these mechanisms, particularly the role of fibrinogen-binding adhesins, is vital for developing targeted, antimicrobial-sparing therapeutics. In this perspective, we examine the strategies uropathogens employ to persist in the catheterized bladder, the corresponding host immune response, and emerging strategies to prevent CAUTI.

The alarming rise of antimicrobial resistance and the declining efficacy of conventional antibiotics emphasize the need for preventive strategies. Within the setting of device-associated infections, antimicrobial peptides (AMPs) have been extensively studied as antimicrobial candidates, owing to their broad-spectrum activity and structural versatility, enabling integration into functional surface coatings. This review provides a comprehensive overview of AMP-based prophylactic approaches, with a particular focus on coatings for medical devices prone to biofilm formation, such as endotracheal tubes, catheters and implants. While surface immobilization of peptides can be accomplished through comparatively straightforward methodologies, the field has progressed toward sophisticated matrix-based systems that enhance stability, biocompatibility and controlled functionality. Yet, despite extensive in vitro and small-scale in vivo studies, clinical translation remains very limited and constrained by several hurdles including regulatory ambiguity and production costs. Overall, this work aims to provide an up-to-date overview of the AMP-based technologies in infection prevention research.