Amir Aliramezani

Prototheca , a genus of unpigmented yeast-like microscopic algae, is an emerging pathogen of humans and animals. Treatment of Prototheca infections is often unsuccessful because the unusual algal biology of these pathogens limits the availability of effective therapeutics. Here, we screened the Pandemic Response Box, a library of 400 compounds with potential anti-infective activity that are either clinically approved or in preclinical development, and identified five promising compounds with anti- Prototheca activity: tafenoquine, OSU-03012, alexidine, ciclopirox, and eberconazole. Characterized alongside amphotericin B, which is currently often used for treatment, these identified compounds displayed potent activity against multiple Prototheca strains and species by inhibiting growth, killing the algae, and disrupting biofilms. Their diverse mechanisms of action included effects on cell walls and membranes, mitochondrial dysfunction, ROS overproduction, metabolic alterations, and induction of apoptosis. Most of the identified compounds were also effective against in vivo Prototheca infection in larval zebrafish, highlighting their translational potential and the possibility of future introduction into clinical practice. IMPORTANCE: This study addresses the emerging threat of infections caused by Prototheca , a group of unusual algae that can cause difficult-to-treat infections in both humans and animals. Current treatment options are limited and often ineffective, highlighting the need to develop new therapeutic strategies, especially as reported cases of Prototheca infections quickly increase. Here, we identified several compounds with strong activity against Prototheca . These agents not only blocked growth but also killed the microorganisms, damaged their biofilms, and reduced infection in an animal model. Importantly, many of the identified compounds are already used clinically for other indications, which raises the possibility of rapid repurposing against Prototheca . Moreover, we identified multiple mechanisms responsible for these compounds’ activity, providing a framework for the future development of even more potent anti- Prototheca therapies.

Clostridioides difficile is a leading cause of healthcare-associated gastrointestinal infection, with outcomes that range widely in severity. The pathogenesis of C. difficile is driven by virulence factors that induce colonic inflammation and epithelial damage. This illness is categorized as an urgent threat, and in recent years, its prevalence has increased, with recurrent episodes occurring in approximately 15-35% of cases. The life cycle of C. difficile infection (CDI) is multifactorial and strongly influenced by antibiotic exposure, host immune responses, the gut microbiota, and microbial metabolites. Disruption of intestinal homeostasis gradually alters the ecological niches of C. difficile and the immunological landscape of the disease. In addition to these risk factors, recurrent C. difficile infection (rCDI) can be exacerbated by certain 'hypervirulent' strains that are more difficult to eradicate. As in many infectious diseases, host immunological responses, particularly in rCDI, appear to play a crucial role in determining recovery versus recurrence. Recent strategies to address this problem include fecal microbiota transplantation (FMT) and novel therapeutic approaches such as polyclonal and monoclonal antibodies. Nevertheless, the immunological mechanisms underlying rCDI remain incompletely understood. A deeper insight into how the immune response develops and functions during rCDI may facilitate the identification of new therapeutic targets. In this review, we summarize current knowledge on C. difficile recurrence and highlight the host immune response in the context of rCDI.

Unpigmented, yeast-like Prototheca algae are emerging pathogens responsible for unusual infections in humans and animals. Their treatment is often unsuccessful, as traditional antifungals and antibacterials show unsatisfactory activity against Prototheca . Therefore, the development of improved drugs that consider the peculiarities of algal biology is needed. Here, we describe a novel anti- Prototheca compound, the 2-methoxy-1,4-naphthoquinone, identified among molecules known to mediate plant and algal allelopathy. The 2-methoxy-1,4-naphthoquinone was highly active in vitro against a range of Prototheca isolates from different species, both planktonically and in biofilms. Its mode of action included the induction of toxic reactive oxygen species, and it targeted energy generation in the pathogen’s mitochondria. It effectively treated Prototheca bovis skin infection in a mouse model, demonstrating translational potential. Altogether, this study not only identified a new effective anti- Prototheca compound, but also identified 1,4-naphthoquinone backbone as a lead structure for further therapeutic development and demonstrated the feasibility of exploring known anti-plant compounds as a source of anti- Prototheca treatments.

In recent years, the incidence of metabolic disorders has exponentially increased worldwide mainly due to the misfunctioning of chemical reactions. Gestational diabetes mellitus (GDM) occurred during pregnancy when placenta prevent absorption of sufficient insulin in mother's body. Although this disorder usually disappears after delivery, it could raise the probability of developing complications in the future. GDM is associated with adverse effects on women and their children, such as obesity, cardiovascular disease, and type 2 diabetes. On the other hand, administration of probiotics as a live microorganism with the wide array of health values could contribute to restore and stabilize gut microbiota and subsequently regulate essential internal functions such as development of immunity. In this review, we focus primarily on some causes and effects of GDM in pregnant women and then Faecalibacterium prasnitzii, the most abundant butyrate-producing bacterium in gut, which have been using as a prominent biomarker in health and disease and also potential anti-inflammatory treatment owing to the production of active molecules.

Introduction: Catheter-associated urinary tract infections (CAUTIs) are among the most common nosocomial infections with different clinical and microbiological characteristics. We studied these characteristics in critically ill patients. Methodology: This research was a cross-sectional study conducted on intensive care unit (ICU) patients with CAUTI. Patients’ demographic and clinical information and laboratory data, including causative microorganisms and antibiotic susceptibility tests, were recorded and analyzed. Finally, the differences between the patients who survived and died were compared. Results: After reviewing 353 ICU cases, 80 patients with CAUTI were finally included in the study. The mean age was 55.9 ± 19.1 years, 43.7% were male and 56.3% were female. The mean length of infection development since hospitalisation and hospital stay were 14.7 (3–90) and 27.8 (5–98) days, respectively. The most common symptom was fever (80%). The microbiological identification showed that the most isolated microorganisms were Multidrug-resistant (MDR) Enterobacteriaceae (75%), Pseudomonas aeruginosa (8.8%), Gram-positive uropathogens (8.8%) and Acinetobacter baumannii (5%). Fifteen patients (18.8%) died among whom infections with A. baumannii (75%) and P. aeruginosa (57.1%) were associated with more death (p = 0.005). Conclusions: Although A. baumannii and P. aeruginosa can be the most important pathogens for death, MDR Enterobacteriaceae are still a serious concern as causes of CAUTIs.

Aim: AFn14R can serve as an ideal target for cancer immunotherapy. Here, a combined bioinformatic and experimental approach was applied to characterize an immunotoxin consisting of single-chain variable fragment antibody that targets Fn14 and a toxin fragment (PE38). Methods & Results: Flow cytometry results showed that the rate of PE38-P4A8 binding to Fn14 was approximately 60 and 40% in HT-29 and A549 cells, respectively. Moreover, 1 ng/µl of immunotoxin was able to lyse approximately 53 and 41% of HT-29 and A549, respectively. PE38-P4A8 showed stability in mouse serum (∼90%) after 3-h incubation. Most importantly, using bioinformatics for determining the structure and function of fusion proteins can be very helpful in designing of experiments. Conclusion: Coupled with bioinformatics, experimental approaches revealed that PE38-P4A8 could be used as a promising therapeutic agent for cancer cells expressing Fn14.