Technical considerations for cost-effective transposon directed insertion-site sequencing (TraDIS).

Transposon directed insertion-site sequencing (TraDIS), a variant of transposon insertion sequencing commonly known as Tn-Seq, is a high-throughput assay that defines essential bacterial genes across diverse growth conditions. However, the variability between laboratory environments often requires laborious, time-consuming modifications to its protocol. In this technical study, we aimed to refine the protocol by identifying key parameters that can impact the complexity of mutant libraries.

Antipsychotic quetiapine alters the mouse fecal resistome by impacting antibiotic efflux, cell membrane, and cell wall synthesis genes.

This study significantly contributes to our understanding of how certain medications can unintentionally contribute to a major global health issue, i.e., antibiotic resistance.

Psychotropic Drugs in the Discussion of Antimicrobial-Resistant Microorganisms.

Psychotropic drugs have long been known to possess antimicrobial activity against several groups of microorganisms. Although this property has been extensively studied both alone and when combined with antibiotics against antimicrobial-resistant bacterial and fungal species, relatively little attention has been given to their ability to contribute to the emergence of antimicrobial resistance (AMR). We have recently reported the acquisition of multidrug resistance in after exposure to gut-relevant concentrations of the antipsychotic quetiapine.

Ceftazidime-avibactam based combinations against carbapenemase producing harboring hypervirulence plasmids.

The combination of carbapenem resistance and hypervirulence in is an emerging and urgent threat due to its potential to resist common antibiotics and cause life-threatening infections in healthy hosts. This study aimed to evaluate the activity of clinically relevant antibiotic regimens against carbapenem-resistant with hypervirulence plasmids and to identify pathways associated with antibiotic tolerance using transcriptomics. We studied two carbapenem-resistant isolates, CDI694 and CDI231, both harboring hypervirulence plasmids.

The Atypical Antipsychotic Quetiapine Promotes Multiple Antibiotic Resistance in Escherichia coli.

Atypical antipsychotic (AAP) medication is a critical tool for treating symptoms of psychiatric disorders. While AAPs primarily target dopamine (D2) and serotonin (5HT2A and 5HT1A) receptors, they also exhibit intrinsic antimicrobial activity as an off-target effect. Because AAPs are often prescribed to patients for many years, a potential risk associated with long-term AAP use is the unintended emergence of bacteria with antimicrobial resistance (AMR).

Pharmacokinetic characterization of carnosol from rosemary (Salvia Rosmarinus) in male C57BL/6 mice and inhibition profile in human cytochrome P450 enzymes.

Rosemary (Salvia Rosmarinus) is a rich source of dietary diterpenes with carnosol as one of the major polyphenols used to standardize rosemary extracts approved as a food preservative, however, at present there is not any information on the murine pharmacokinetic profile of carnosol or its potential for drug interactions. The present study utilizes cell-free, cell-based, and animal-based experiments to define the pharmacokinetic profile of the food based phytochemical carnosol. Mice were administered carnosol (100 mg/kg body weight) by oral gavage and plasma levels were analyzed by LC-MS/MS to establish a detailed pharmacokinetic profile.

Potential Implications of Gut Microbiota in Drug Pharmacokinetics and Bioavailability.

Gut microbial communities are capable of enzymatically transforming pharmaceutical compounds into active, inactive, and toxic metabolites, thus potentially affecting the pharmacokinetics and bioavailability of orally administered medications. Our understanding of the impact and clinical relevance of how gut microbial communities can directly and indirectly affect drug metabolism and, ultimately, clinical outcomes, is limited. Interindividual variability of gut microbial composition may partially explain differences observed in drug efficacy and toxicity in certain patient populations.

The Gut Microbiome in Bipolar Disorder and Pharmacotherapy Management.

The gut microbiome is a complex and dynamic community of commensal, symbiotic, and pathogenic microorganisms that exist in a bidirectional relationship with the host. Bacterial functions in the gut play a critical role in healthy host functioning, and its disruption can contribute to many medical conditions. The relationship between gut microbiota and the brain has gained attention in mental health due to the mounting evidence supporting the association of gut bacteria with mood and behavior.

Preclinical and Clinical Sex Differences in Antipsychotic-Induced Metabolic Disturbances: A Narrative Review of Adiposity and Glucose Metabolism.

Antipsychotic (AP) medications are associated with an increased risk of developing metabolic side effects including weight gain, type 2 diabetes (T2D), dyslipidemia, and hypertension. In the majority of clinical studies, females on APs are noted to gain more weight, and are more likely to be diagnosed with metabolic syndrome when compared to males. However, the data is less clear when comparing sex disparities associated with other specific AP-induced metabolic risk factors.

Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of .

The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including spp. To evaluate their activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68  clinical isolates well characterized for azole resistance mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 and VT-1598 demonstrated potent activity (geometric mean MICs ≤0.

The Evolution of Azole Resistance in Sterol 14α-Demethylase (CYP51) through Incremental Amino Acid Substitutions.

Recombinant CYP51 (CaCYP51) proteins containing 23 single and 5 double amino acid substitutions found in clinical strains and the wild-type enzyme were expressed in and purified by Ni-nitrilotriacetic acid agarose chromatography. Catalytic tolerance to azole antifungals was assessed by determination of the concentration causing 50% enzyme inhibition (IC) using CYP51 reconstitution assays. The greatest increase in the IC compared to that of the wild-type enzyme was observed with the five double substitutions Y132F+K143R (15.

Effects of Atypical Antipsychotic Treatment and Resistant Starch Supplementation on Gut Microbiome Composition in a Cohort of Patients with Bipolar Disorder or Schizophrenia.

Study Objective: Previous studies identified shifts in gut microbiota associated with atypical antipsychotic (AAP) treatment that may link AAPs to metabolic burden. Dietary prebiotics such as resistant starch may be beneficial in obesity and glucose regulation, but little is known mechanistically about their ability to modify gut microbiota in AAP-treated individuals. This investigation was undertaken to delineate mechanistically the effects of AAP treatment and resistant starch supplementation on gut microbiota in a psychiatric population.

Atypical Antipsychotic Exposure May Not Differentiate Metabolic Phenotypes of Patients with Schizophrenia.

Study Objective: Patients with schizophrenia are known to have higher rates of metabolic disease than the general population. Contributing factors likely include lifestyle and atypical antipsychotic (AAP) use, but the underlying mechanisms are unknown. The objective of this study was to identify metabolomic variability in adult patients with schizophrenia who were taking AAPs and grouped by fasting insulin concentration, our surrogate marker for metabolic risk.

Cardiovascular Pharmacogenomics and Cognitive Function in Patients with Schizophrenia.

The authors sought to examine the impact of multiple risk alleles for cognitive dysfunction and cardiovascular disease risk on cognitive function and to determine if these relationships varied by cognitive reserve (CR) or concomitant medication use in patients with schizophrenia. They conducted a cross-sectional study in ambulatory mental health centers. A total of 122 adults with a schizophrenia spectrum diagnosis who were maintained on a stable antipsychotic regimen for at least 6 months before study enrollment were included.

Interaction Between Atypical Antipsychotics and the Gut Microbiome in a Bipolar Disease Cohort.

Objectives: The atypical antipsychotic (AAP) class is often associated with metabolic disease, but the mechanistic underpinnings of this risk are not understood. Due to reports linking gut bacteria function to metabolic disease, we hypothesize that AAP treatment in adults results in gut dysbiosis potentiating metabolic criteria. This report describes recent findings linking AAP treatment with differences in gut microbiota communities in a human cohort with bipolar disorder (BD).

The gut microbiome composition associates with bipolar disorder and illness severity.

The gut microbiome is emerging as an important factor in regulating mental health yet it remains unclear what the target should be for psychiatric treatment. We aimed to elucidate the complement of the gut-microbiome community for individuals with bipolar disorder relative to controls; and test for relationships with burden of disease measures. We compared the stool microbiome from individuals with bipolar disorder (n = 115) and control subjects (n = 64) using 16S ribosomal RNA (rRNA) gene sequence analysis.

Interaction between COMT rs5993883 and second generation antipsychotics is linked to decreases in verbal cognition and cognitive control in bipolar disorder.

Background: Second generation antipsychotics (SGAs) are increasingly utilized in Bipolar Disorder (BD) but are potentially associated with cognitive side effects. Also linked to cognitive deficits associated with SGA-treatment are catechol-O-methyltransferase (COMT) gene variants. In this study, we examine the relationship between cognition in SGA use and COMT rs5993883 in cohort sample of subjects with BD.

The Microbiome in Mental Health: Potential Contribution of Gut Microbiota in Disease and Pharmacotherapy Management.

The gut microbiome is composed of ~10(13) -10(14) microbial cells and viruses that exist in a symbiotic bidirectional communicative relationship with the host. Bacterial functions in the gut have an important role in healthy host metabolic function, and dysbiosis can contribute to the pathology of many medical conditions. Alterations in the relationship between gut microbiota and host have gained some attention in mental health because new evidence supports the association of gut bacteria to cognitive and emotional processes.

Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans.

In Candida albicans, the ERG11 gene encodes lanosterol demethylase, the target of the azole antifungals. Mutations in ERG11 that result in an amino acid substitution alter the abilities of the azoles to bind to and inhibit Erg11, resulting in resistance. Although ERG11 mutations have been observed in clinical isolates, the specific contributions of individual ERG11 mutations to azole resistance in C.

UPC2 is universally essential for azole antifungal resistance in Candida albicans.

In Candida albicans, the transcription factor Upc2 is central to the regulation of ergosterol biosynthesis. UPC2-activating mutations contribute to azole resistance, whereas disruption increases azole susceptibility. In the present study, we investigated the relationship of UPC2 to fluconazole susceptibility, particularly in azole-resistant strains.

Gain-of-function mutations in UPC2 are a frequent cause of ERG11 upregulation in azole-resistant clinical isolates of Candida albicans.

In Candida albicans, Upc2 is a zinc-cluster transcription factor that targets genes, including those of the ergosterol biosynthesis pathway. To date, three documented UPC2 gain-of-function (GOF) mutations have been recovered from fluconazole-resistant clinical isolates that contribute to an increase in ERG11 expression and decreased fluconazole susceptibility. In a group of 63 isolates with reduced susceptibility to fluconazole, we found that 47 overexpressed ERG11 by at least 2-fold over the average expression levels in 3 unrelated fluconazole-susceptible strains.

The role of voriconazole in the treatment of central nervous system blastomycosis.

Background: Blastomycosis is an endemic mycosis caused by the dimorphic fungus Blastomyces dermatitidis. Although this disease primarily involves the lungs, the clinical spectrum of blastomycosis can range from subclinical infection to extrapulmonary dissemination. The central nervous system (CNS) form of blastomycosis is primarily treated with an amphotericin B formulation, but associated toxicities of this agent preclude its use in some patients.