extracellular vesicles are a broad and permissive antimicrobial packaging and delivery system.

are the primary source of bioactive specialized metabolites used in research and medicine, including many antimicrobials. These are presumed to be secreted and function as freely soluble compounds. However, increasing evidence suggests that extracellular vesicles are an alternative secretion system.

Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation.

Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections.

High-Throughput Chemical Screen Identifies a 2,5-Disubstituted Pyridine as an Inhibitor of Candida albicans Erg11.

Fungal infections contribute to over 1.5 million deaths annually, with Candida albicans representing one of the most concerning human fungal pathogens. While normally commensal in nature, compromise of host immunity can result in C.

Biology and applications of co-produced, synergistic antimicrobials from environmental bacteria.

Environmental bacteria, such as Streptomyces spp., produce specialized metabolites that are potent antibiotics and therapeutics. Selected specialized antimicrobials are co-produced and function together synergistically.

Cytosolic and Mitochondrial Hsp90 in Cytokinesis, Mitochondrial DNA Replication, and Drug Action in Trypanosoma brucei.

Trypanosoma brucei subspecies cause African sleeping sickness in humans, an infection that is commonly fatal if not treated, and available therapies are limited. Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors have potent and vivid activity against bloodstream-form trypanosomes. Hsp90s are phylogenetically conserved and essential catalysts that function at the crux of cell biology, where they ensure the proper folding of proteins and their assembly into multicomponent complexes.

Predicting antimicrobial mechanism-of-action from transcriptomes: A generalizable explainable artificial intelligence approach.

To better combat the expansion of antibiotic resistance in pathogens, new compounds, particularly those with novel mechanisms-of-action [MOA], represent a major research priority in biomedical science. However, rediscovery of known antibiotics demonstrates a need for approaches that accurately identify potential novelty with higher throughput and reduced labor. Here we describe an explainable artificial intelligence classification methodology that emphasizes prediction performance and human interpretability by using a Hierarchical Ensemble of Classifiers model optimized with a novel feature selection algorithm called Clairvoyance; collectively referred to as a CoHEC model.

Pulse Dosing of Antibiotic Enhances Killing of a Biofilm.

Biofilms are highly tolerant to antibiotics and underlie the recalcitrance of many chronic infections. We demonstrate that mature biofilms can be substantially sensitized to the treatment by pulse dosing of an antibiotic - in this case, oxacillin. Pulse (periodic) dosing was compared to continuous application of antibiotic and was studied in a novel flow system which allowed for robust biofilm growth and tractable pharmacokinetics of dosing regimens.

Author Correction: A new antibiotic selectively kills Gram-negative pathogens.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling.

Antimicrobial resistance (AMR) is an ever-growing public health problem worldwide. The low rate of antibiotic discovery coupled with the rapid spread of drug-resistant bacterial pathogens is causing a global health crisis. To facilitate the drug discovery processes, we present a large-scale study of reference antibiotic challenge bacterial transcriptome profiles, which included 37 antibiotics across 6 mechanisms of actions (MOAs) and provide an economical approach to aid in antimicrobial dereplication in the discovery process.

A new antibiotic selectively kills Gram-negative pathogens.

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s.

Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics.

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block L-allo-Enduracidine in 30-gram scale in just one hour  and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin.

Optimal kinetic exposures for classic and candidate antitrypanosomals.

Objectives: Efficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomals in vitro.

Methods: An in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei.

Creative Arts Interventions to Address Depression in Older Adults: A Systematic Review of Outcomes, Processes, and Mechanisms.

Depression experienced by older adults is proving an increasing global health burden, with rates generally 7% and as high as 27% in the USA. This is likely to significantly increase in coming years as the number and proportion of older adults in the population rises all around the world. Therefore, it is imperative that the effectiveness of approaches to the prevention and treatment of depression are understood.

Model System Identifies Kinetic Driver of Hsp90 Inhibitor Activity against African Trypanosomes and Plasmodium falciparum.

Hsp90 inhibitors, well studied in the laboratory and clinic for antitumor indications, have promising activity against protozoan pathogens, including which causes African sleeping sickness, and the malaria parasite, To progress these experimental drugs toward clinical use, we adapted an dynamic hollow-fiber system and deployed artificial pharmacokinetics to discover the driver of their activity: either concentration or time. The activities of compounds from three major classes of Hsp90 inhibitors in development were evaluated against trypanosomes. In all circumstances, the activities of the tested Hsp90 inhibitors were concentration driven.

Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin.

Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine.

Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo.

African sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is universally fatal if untreated, and current drugs are limited by severe toxicities and difficult administration. New antitrypanosomals are greatly needed. Heat shock protein 90 (Hsp90) is a conserved and ubiquitously expressed molecular chaperone essential for stress responses and cellular signaling.

Analogs of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases.

Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs.

Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.

The risk of emergency room treatment due to overdose in injection drug users.

This cohort study was conducted to identify risk factors for lifetime emergency room treatment due to overdose in injection drug users. Data of 1049 patients on admission for opioid detoxification were analyzed. More than every third injection drug user (34.

Efficacy of a polyethylene glycol marker system in urine drug screening in an opiate substitution program.

Aims: Screening for concomitant drug consumption is necessary in opiate substitution therapy of opiate-dependent patients. Adulteration of samples is a common problem in this setting. A recently developed polyethylene glycol marker system allows reliable identification of urine samples.

Factors associated with exposure to hepatitis B virus in injection drug users.

This study was undertaken to describe factors associated with exposure to the hepatitis B virus (HBV) in treated injection drug users to better aim prevention and care in high risk subgroups. The naturalistic study was conducted in Munich, Germany, and 1,018 patients who ever shared needles admitted for opioid detoxification were included. Sociodemographic, drug and drug treatment related variables and the virological status (HCV, HIV) were included in the bivariate and multiple logistic regression analysis.

Co-consumption of benzodiazepines in heroin users, methadone-substituted and codeine-substituted patients.

Concomitant consumption of benzodiazepines (BZDs) and opioids is a major problem in patients with opioid dependence. It may have substantial impact on morbidity, mortality and clinical course. The current retrospective study aims to determine whether there are differences in the additional use of BZDs among addicts regularly taking methadone or codeine medications in treatment and untreated addicts injecting heroin.

Risk Factors and predictors of human immunodeficiency virus infection among injection drug users.

Background/aim: Injection drug users (IDUs) have a high risk of acquiring an infection with the human immunodeficiency virus (HIV). To improve counseling and prevention, a better understanding of risk factors and predictors for an infection must be gained. This retrospective study has the aim to determine the risk factors for acquisition of HIV infection other than sharing of needles/syringes.