Machine learning-assisted high-throughput screening for Anti-MRSA compounds.

Background: Antimicrobial resistance is a major public health threat, and new agents are needed. Computational approaches have been proposed to reduce the cost and time needed for compound screening.

Aims: A machine learning (ML) model was developed for the in silico screening of low molecular weight molecules.

Auranofin coated catheters inhibit bacterial and fungal biofilms in a murine subcutaneous model.

Microbe entry through catheter ports can lead to biofilm accumulation and complications from catheter-related bloodstream infection and ultimately require antimicrobial treatment and catheter replacement. Although strides have been made with microbial prevention by applying standardized antiseptic techniques during catheter implantation, both bacterial and fungal microbes can present health risks to already sick individuals. To reduce microbial adhesion, murine and human catheters were coated with polyurethane and auranofin using a dip coating method and compared to non-coated materials.

The Protective Role of Interleukin 17A in Acinetobacter baumannii Pneumonia Is Associated with Candida albicans in the Airway.

Recent studies have found that the coexistence of fungi and bacteria in the airway may increase the risk of infection, contribute to the development of pneumonia, and increase the severity of disease. Interleukin 17A (IL-17A) plays important roles in host resistance to bacterial and fungal infections. The objective of this study was to determine the effects of IL-17A on Acinetobacter baumannii-infected rats with a previous Candida albicans airway inoculation.

A Substituted Diphenyl Amide Based Novel Scaffold Inhibits Virulence in a Infection Model.

Antimicrobial compounds can combat microbes through modulating host immune defense, inhibiting bacteria survival and growth, or through impeding or inhibiting virulence factors. In the present study, a panel of substituted diphenyl amide compounds previously found to disrupt bacterial quorum sensing were investigated and several were found to promote survival in the model when provided therapeutically to treat a Gram-positive bacterial infection from methicillin-resistant strain MW2. Out of 21 tested compounds, -4-Methoxyphenyl-3-(4-methoxyphenyl)-propanamide (AMI 82B) was the most potent at disrupting .

The Anti-Biofilm Efficacy of Caffeic Acid Phenethyl Ester (CAPE) and a Murine Model of Oral Candidiasis.

is the main fungal species associated with the development of oral candidiasis. Currently, therapeutic options for these infections are limited by the adverse effects of antifungal drugs and by the emergence of drug resistant strains. Thus, the development of new antifungal agents is needed for the prevention and treatment of oral infections.

Thioredoxin Reductase Is a Valid Target for Antimicrobial Therapeutic Development Against Gram-Positive Bacteria.

There is a drought of new antibacterial compounds that exploit novel targets. Thioredoxin reductase (TrxR) from the Gram-positive bacterial antioxidant thioredoxin system has emerged from multiple screening efforts as a potential target for auranofin, ebselen, shikonin, and allicin. Auranofin serves as the most encouraging proof of concept drug, demonstrating TrxR inhibition can result in bactericidal effects and inhibit Gram-positive bacteria in both planktonic and biofilm states.

Current and promising pharmacotherapeutic options for candidiasis.

:  spp. are commensal yeasts capable of causing infections such as superficial, oral, vaginal, or systemic infections. Despite medical advances, the antifungal pharmacopeia remains limited and the development of alternative strategies is needed.

Probiotic Effects of Lactobacillus paracasei 28.4 to Inhibit Streptococcus mutans in a Gellan-Based Formulation.

Streptococcus mutans is considered to be a major bacterium involved in dental caries, and the control of virulence mechanisms is fundamental to prevent disease. Probiotics present a promising preventive method; however, the use of probiotics requires its incorporation into delivery materials to facilitate oral colonization. Thus, we performed a comprehensive study examining preventive effects of Lactobacillus paracasei 28.

The Postbiotic Activity of 28.4 Against .

has emerged as a medically important pathogen with considerable resistance to antifungal agents. The ability to produce biofilms is an important pathogenicity feature of this species that aids escape of host immune responses and antimicrobial agents. The objective of this study was to verify antifungal action using and models of the 28.

Secreted Products Inhibit Induced Oral Candidiasis.

In the oral cavity, species form mixed biofilms with , a pathogenic bacterium that can secrete molecules with antifungal activity. In this study, we extracted and fractioned culture filtrate of , seeking antifungal agents capable of inhibiting the biofilms, filamentation, and candidiasis by . Active UA159 supernatant filtrate components were extracted via liquid-liquid partition and fractionated on a C-18 silica column to resolve fraction 1 (SM-F1) and fraction 2 (SM-F2).

Caenorhabditis elegans mounts a p38 MAPK pathway-mediated defence to Cutibacterium acnes infection.

Cutibacterium acnes is capable of inducing inflammation in acne and can lead to a chronic prostatic infection. The diverse pathogenicity among different strains of C. acnes has been presented, but simple appropriate animal models for the evaluation of this bacterium are lacking.

The monoclonal antibody Ca37, developed against Candida albicans alcohol dehydrogenase, inhibits the yeast in vitro and in vivo.

Candida albicans is a commensal yeast able to cause life threatening invasive infections particularly in immunocompromised patients. Despite the availability of antifungal treatments, mortality rates are still unacceptably high and drug resistance is increasing. We, therefore, generated the Ca37 monoclonal antibody against the C.

Anti-MRSA agent discovery using Caenorhabditis elegans-based high-throughput screening.

Staphylococcus aureus is a leading cause of hospital- and community-acquired infections. Despite current advances in antimicrobial chemotherapy, the infections caused by S. aureus remain challenging due to their ability to readily develop resistance.

Development of Probiotic Formulations for Oral Candidiasis Prevention: Gellan Gum as a Carrier To Deliver Lactobacillus paracasei 28.4.

Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and it is necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeted for local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food additive, with a probiotic and investigated its antifungal activity against 28.

Regulates the Hog1-MAPK Pathway and Is Involved in Response to Hyperosmotic Stress.

is the most common fungal pathogen and relies on the Hog1-MAPK pathway to resist osmotic stress posed by the environment or during host invasions. Here, we investigated the role of in response to osmotic stress. Testing a Δ/Δ mutant, we found it was sensitive to osmotic stress.

The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant .

Antimicrobial drug discovery against drug-resistant bacteria is an urgent need. Beyond agents with direct antibacterial activity, anti-virulent molecules may also be viable compounds to defend against bacterial pathogenesis. Using a high throughput screen (HTS) that utilized infected with methicillin-resistant (MRSA) strain of MW2, we identified 4-(1,3-dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)phenol (BIP).

A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant .

Treatment of infections is complicated by the development of antibiotic tolerance, a consequence of the ability of to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes.

Auranofin is an effective agent against clinical isolates of .

The orphan drug auranofin was recently found to exhibit antimicrobial properties. We explored the efficacy of auranofin by evaluating the minimal inhibitory concentration against a collection of over 500 clinical isolates derived from multiple institutions, inclusive of drug resistant strains. Our evaluation also included continuous exposure of bacteria to auranofin.

Auranofin Releasing Antibacterial and Antibiofilm Polyurethane Intravascular Catheter Coatings.

Intravascular catheter related bloodstream infections (CRBSIs) are a leading cause of hospital-acquired infections worldwide, resulting not only in the burden of cost and morbidity for patients but also in the over-consumption of medical resources for hospitals and health care organizations. In this study, a novel auranofin releasing antibacterial and antibiofilm polyurethane (PU) catheter coating was developed and investigated for future use in preventing CRBSIs. Auranofin is an antirheumatic drug with recently identified antimicrobial properties.

Rapid Isolation and Concentration of Pathogenic Fungi Using Inertial Focusing on a Chip-Based Platform.

Systemic infections remain a leading cause of nosocomial infections in the United States and worldwide. Many challenges remain in achieving rapid, direct diagnosis of fungal bloodstream infections due to limitations of conventional diagnostic methods that continue to demonstrate poor sensitivity, prolonged culture times that lead to delayed treatment, and detection variability between tests that compromises result reproducibility. Despite advancements in technology, mortality, and cost of care presented by blood stream infection with spp.

Anti- Activity of Thiazolylhydrazone Derivatives in Invertebrate and Murine Models.

Candidiasis is an opportunistic fungal infection with being the most frequently isolated species. Treatment of these infections is challenging due to resistance that can develop during therapy, and the limited number of available antifungal compounds. Given this situation, the aim of this study was to evaluate the antifungal activity of four thiazolylhydrazone compounds against .

Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions.

Aging presents a significant risk factor for Clostridium difficile infection (CDI). A disproportionate number of CDIs affect individuals in long-term care facilities compared with the general population, likely due to the vulnerable nature of the residents and shared environment. Review of the literature cites a number of underlying medical conditions such as the use of antibiotics, proton pump inhibitors, chemotherapy, renal disease and feeding tubes as risk factors.

Galleria mellonella experimental model for bat fungal pathogen Pseudogymnoascus destructans and human fungal pathogen Pseudogymnoascus pannorum.

Laboratory investigations of the pathogenesis of Pseudogymnoascus destructans, the fungal causal agent of bat White Nose Syndrome (WNS), presents unique challenges due to its growth requirements (4°-15°C) and a lack of infectivity in the current disease models. Pseudogymnoascus pannorum is the nearest fungal relative of P. destructans with wider psychrophilic - physiological growth range, and ability to cause rare skin infections in humans.

Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters.

Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S.

SDH2 is involved in proper hypha formation and virulence in Candida albicans.

Aim: To investigate the role of SDH2 in Candida albicans filamentation and virulence.

Materials & Methods: Caenorhabditis elegans and mouse candidiasis models were used to assess the virulence of a sdh2Δ/Δ mutant. Various hypha-inducing media were used to evaluate the hyphal development of C.