Brilacidin, a novel antifungal agent against .

Unlabelled: causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against .

Membrane Phenotypic, Metabolic and Genotypic Adaptations of Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures.

The subgroup of viridans group streptococci are important human pathogens. We previously showed that a substantial portion of strains (>25%) are 'destined' to develop rapid, high-level, and stable daptomycin (DAP) resistance (DAP-R) during DAP exposures in vitro. Such DAP-R is often accompanied by perturbations in distinct membrane phenotypes and metabolic pathways.

Combinations of Daptomycin plus Ceftriaxone, but Not Ascending Daptomycin Dose-Regimens, Are Effective in Experimental Endocarditis Caused by Streptococcus mitis Strains: Target Tissue Clearances and Prevention of Emergence of Daptomycin-Resistance.

The Streptococcus mitis subgroup of the viridans group streptococci (VGS) are the most common cause of infective endocarditis (IE) in many parts of the world. These organisms are frequently resistant to standard β-lactams (e.g.

Development of phimosis as an adverse drug reaction to capecitabine with irinotecan.

We present a case of a 32-year-old male who developed capecitabine-induced phimosis which resolved spontaneously without the need for circumcision within a few days of discontinuation of chemotherapy. The patient was on capecitabine with irinotecan chemotherapy for peritoneal metastasis from adenocarcinoma of the lower esophagus. A detailed literature review showed a few case reports with penile and scrotal erythema, ulceration, and swelling along with hand-foot syndrome, but none reported the occurrence of phimosis with spontaneous resolution.

Activity of the Lactate Dehydrogenase Inhibitor Oxamic Acid against the Fermentative Bacterium : Bactericidal Effects and Prevention of Daptomycin Resistance In Vitro and in an Ex Vivo Model.

is a fermentative bacterium that relies on lactate dehydrogenase to balance its redox poise and keep glycolysis active. Metabolomic analysis of an in vitro-derived daptomycin-resistant (DAP-R) strain (351-D10) revealed differences in glucose catabolism relative to its DAP-susceptible (DAP-S) parental strain, 351. Metabolic changes associated with the transition to this DAP-R phenotype suggested that inhibiting glycolysis could alter DAP susceptibility.

Interstitial cystitis/bladder pain syndrome (IC/BPS): Single-center 20 year experience and treatment results in India.

Objectives: Interstitial cystitis/bladder pain syndrome (IC/BPS) is an enigmatic disease that is difficult to treat. Even among physicians, the prevalent belief is that patients do not improve over time. In this study, we retrospectively reviewed our experience and treatment results for patients diagnosed with IC/BPS at our clinic in India over the past 20 years.

Synergy Mechanisms of Daptomycin-Fosfomycin Combinations in Daptomycin-Susceptible and -Resistant Methicillin-Resistant Staphylococcus aureus: , , and Metrics.

Increased usage of daptomycin (DAP) for methicillin-resistant Staphylococcus aureus (MRSA) infections has led to emergence of DAP-resistant (DAP-R) strains, resulting in treatment failures. DAP-fosfomycin (Fosfo) combinations are synergistically active against MRSA, although the mechanism(s) of this interaction is not fully understood. The current study explored four unique but likely interrelated activities of DAP-Fosfo combinations: (i) synergistic killing, (ii) prevention of evolution of DAP-R, (iii) resensitization of already DAP-R subpopulations to a DAP-susceptible (DAP-S) phenotype, and (iv) perturbations of specific cell envelope phenotypes known to correlate with DAP-R in MRSA.

β-Lactam-Induced Cell Envelope Adaptations, Not Solely Enhanced Daptomycin Binding, Underlie Daptomycin-β-Lactam Synergy in Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious clinical threat due to innate virulence properties, high infection rates, and the ability to develop resistance to multiple antibiotics, including the lipopeptide daptomycin (DAP). The acquisition of DAP resistance (DAP-R) in MRSA has been linked with several characteristic alterations in the cell envelope. Clinical treatment of DAP-R MRSA infections has generally involved DAP-plus-β-lactam combinations, although definable synergy of such combinations varies in a strain-dependent as well as a β-lactam-dependent manner.

Cell Membrane Adaptations Mediate β-Lactam-Induced Resensitization of Daptomycin-Resistant (DAP-R) In Vitro.

The reversal of daptomycin resistance in MRSA to a daptomycin-susceptible phenotype following prolonged passage in selected β-lactams occurs coincident with the accumulation of multiple point mutations in the gene. MprF regulates surface charge by modulating the content and translocation of the positively charged cell membrane phospholipid, lysyl-phosphatidylglycerol (LPG). The precise cell membrane adaptations accompanying such β-lactam-induced perturbations are unknown.

Mechanistic Fingerprinting Reveals Kinetic Signatures of Resistance to Daptomycin and Host Defense Peptides in .

infections are increasingly prevalent in specific populations, including neutropenic cancer and endocarditis patients. strains have a propensity to evolve rapid, high-level and durable resistance to daptomycin (DAP-R) in vitro and in vivo, although the mechanism(s) involved remain incompletely defined. We examined mechanisms of DAP-R versus cross-resistance to cationic host defense peptides (HDPs), using an isogenic strain-pair: (i) DAP-susceptible (DAP-S) parental 351-WT (DAP MIC = 0.

Ethical Practices and Legal Challenges in Mental Health Research.

Considerations of justice and concern for well-being support conducting mental health research and addressing ethical concerns specific to mental health research are critical. We discuss these concerns, provide recommendations to enable the ethical conduct of mental health research, and argue that participants' interests should be given primary weight in resolving apparent dilemmas. We also comment on provisions of two legislative actions in India relevant to mental health research: Rights of Persons with Disability Act 2016 and the Mental Health Care Act 2017.

Impact of Bicarbonate on PBP2a Production, Maturation, and Functionality in Methicillin-Resistant (MRSA).

Certain methicillin-resistant (MRSA) strains exhibit β-lactam-susceptibility , and in the presence of NaHCO (NaHCO-responsive MRSA). Herein, we investigate the impact of NaHCO on factors required for PBP2a functionality. Prototype NaHCO-responsive and -nonresponsive MRSA strains (as defined ) were assessed for the impact of NaHCO on: expression of genes involved in PBP2a production-maturation pathways (, , , , , , and ); membrane PBP2a and PrsA protein content; and membrane carotenoid content.

Strain-Specific Adaptations of to Serial In Vitro Passage in Daptomycin (DAP): Genotypic and Phenotypic Characteristics.

Viridans group streptococci (VGS), especially the subgroup, are pivotal pathogens in a variety of invasive endovascular infections, including "toxic shock" in neutropenic cancer patients and infective endocarditis (IE). Previously, we showed that the serial in vitro passage of strains in sublethal daptomycin (DAP) resulted in rapid, high-level and stable DAP-resistance (DAP-R), which is accompanied by distinct changes in several genotypic and phenotypic signatures: (1) the disappearance of two key membrane phospholipids, phosphatidylglycerol (PG) and cardiolipin (CL); (2) increased membrane fluidity; (3) increased positive surface charge; (4) single nucleotide polymorphisms (SNPs) in two loci involved in CL biosynthesis (); and (5) DAP hyperaccumulation. The current study examined these same metrics following in vitro serial DAP passages of a separate well-characterized bloodstream isolate (SF100).

Prolonged Exposure to β-Lactam Antibiotics Reestablishes Susceptibility of Daptomycin-Nonsusceptible Staphylococcus aureus to Daptomycin.

Daptomycin-nonsusceptible (DAP-NS) often exhibits gain-in-function mutations in the gene (involved in positive surface charge maintenance). Standard β-lactams, although relatively inactive against methicillin-resistant (MRSA), may prevent the emergence of mutations and DAP-NS. We determined if β-lactams might also impact DAP-NS isolates already possessing an mutation to revert them to DAP-susceptible (DAP-S) phenotypes and, if so, whether this is associated with specific penicillin-binding protein (PBP) targeting.

Metabolic changes associated with adaptive resistance to daptomycin in Streptococcus mitis-oralis.

Background: Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens. They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.

Informed consent in psychiatry outpatients.

Background & Objectives: Comprehension and process of consent are important for persons with mental illness as they may not be impaired in considering research participation. The American Psychiatric Association developed a detailed Cultural Formulation Interview (CFI). The present study was a part of field testing of CFI, aimed to standardize cultural information affecting the patients' management in India.

Hunner lesion disease differs in diagnosis, treatment and outcome from bladder pain syndrome: an ESSIC working group report.

There is confusion about the terms of bladder pain syndrome (BPS) and Interstitial Cystitis (IC). The European Society for the Study of IC (ESSIC) classified these according to objective findings [9]. One phenotype, Hunner lesion disease (HLD or ESSIC 3C) differs markedly from other presentations.

Why parents consent to their children's participation in genetic research: A study of parental decision making.

Parents need to be asked to provide informed consent on behalf of their child for participation in genetic research. Decision making for such parents is difficult because ethical challenges in paediatric genetic research studies are different from similar adult studies. This paper focuses on interviews conducted with parents who were asked to consent to their children's participation (or not) in a genetic research study of intellectual disability and/or autism.

Proteomic and Membrane Lipid Correlates of Reduced Host Defense Peptide.

We previously described a transposon mutant in strain SH1000 that exhibited reduced susceptibility to cationic thrombin-induced platelet microbicidal proteins (tPMPs). The transposon insertion site was mapped to the gene , the staphylococcal orthologue. Hence, further studies have been performed to understand how this mutation impacts susceptibility to tPMP, by comparing proteomics profiling and membrane lipid analyses of the parent vs.

Intravesical tacrolimus in treatment of intractable interstitial cystitis/bladder pain syndrome - A pilot study.

Aims: Interstitial cystitis/Bladder pain syndrome (IC/BPS) is a chronic condition with limited effectiveness of current treatments without any cure. Cyclosporine A is effective in intractable cases of BPS/IC. Tacrolimus has same mechanism of action.

Metabolic interventions for the prevention and treatment of daptomycin non-susceptibility in Staphylococcus aureus.

Background: A major developing problem in the treatment of Staphylococcus aureus infections is the emergence of resistance during treatment with daptomycin. Previous metabolomic analyses of isogenic S. aureus strains prior to and after evolution into a daptomycin non-susceptible (DapNS) state provided important metabolic information about this transition (e.

Daptomycin Dose-Ranging Evaluation with Single-Dose versus Multidose Ceftriaxone Combinations against Streptococcus mitis in an Simulated Endocarditis Vegetation Model.

The viridans group streptococci (VGS) are a heterogeneous group of organisms which are important components of the normal human oral flora. Among the VGS, the subgroup is one of the most common causes of infective endocarditis (IE). Daptomycin (DAP) is a potential alternative therapeutic option for invasive infections, given high rates of β-lactam resistance and vancomycin tolerance in such strains.

Comparative Efficacies of Linezolid vs. Tedizolid in an Experimental Murine Model of Vancomycin-Resistant Enterococcal (VRE) Bacteremia.

Tedizolid () is an oxazolidinone derivative which demonstrates bacteriostatic activity through inhibition of protein synthesis. We compared the efficacies of TZD and an earlier-generation oxazolidinone, linezolid (), in an experimental murine model of bacteremia caused by two VRE strains (one each and ). LZD exhibited significantly better efficacy in terms of reduced VRE blood and target tissue densities than TZD in this model.

Gain-of-Function Mutations in the Phospholipid Flippase MprF Confer Specific Daptomycin Resistance.

Daptomycin, a calcium-dependent lipopeptide antibiotic whose full mode of action is still not entirely understood, has become a standard-of-care agent for treating methicillin-resistant (MRSA) infections. Daptomycin-resistant (DAP-R) mutants emerge during therapy, featuring isolates which in most cases possess point mutations in the gene. MprF is a bifunctional bacterial resistance protein that synthesizes the positively charged lipid lysyl-phosphatidylglycerol (LysPG) and translocates it subsequently from the inner membrane leaflet to the outer membrane leaflet.

Membrane trafficking of the bacterial adhesin GspB and the accessory Sec transport machinery.

The serine-rich repeat (SRR) glycoproteins of Gram-positive bacteria are large, cell wall-anchored adhesins that mediate binding to many host cells and proteins and are associated with bacterial virulence. SRR glycoproteins are exported to the cell surface by the accessory Sec (aSec) system comprising SecA2, SecY2, and 3-5 additional proteins (Asp1 to Asp5) that are required for substrate export. These adhesins typically have a 90-amino acid-long signal peptide containing an elongated N-region and a hydrophobic core.