Targeting Vancomycin-Resistant (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric Cholic Acid-Peptide Conjugates.

Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE.

Hydrophobicity of Cholic Acid-Derived Amphiphiles Dictates the Antimicrobial Specificity.

The unique structural components of cell membranes of Gram-positive bacteria, Gram-negative bacteria, and mycobacteria provide an excellent therapeutic target for developing highly specific antimicrobials. Here, we report the synthesis of nine cholic acid (CA)-derived amphiphiles, where three hydroxyl groups of CA were tethered to dimethylamino pyridine and the C24-carboxyl group was conjugated with different alkyl chains. Structure-activity investigations revealed that amphiphile harboring a methyl group has antimicrobial activity against mycobacterial species.

Development of a Highly Specific, Selective, and Sensitive Fluorescent Probe for Detection of Mycobacteria in Human Tissues.

Tuberculosis (TB), including extrapulmonary TB, is responsible for more than one million deaths in a year worldwide. Existing methods of mycobacteria detection have poor sensitivity, selectivity, and specificity, especially in human tissues. Herein, the synthesis of a cholic acid-derived fluorescent probe (P4) that can specifically stain the mycobacterium species is presented.

Cholic-Acid-Derived Amphiphiles Can Prevent and Degrade Fungal Biofilms.

Infections caused by fungal species via their existence as biofilms on medical devices can cause organ damage via candidiasis and candidemia. Different species like can pose a serious threat by resisting host's immune system and by developing drug resistance against existing antimycotic agents. Therefore, targeting of fungal membranes can be used as an alternative strategy to combat the fungal infections.

Foliar Application or Seed Priming of Cholic Acid-Glycine Conjugates can Mitigate/Prevent the Rice Bacterial Leaf Blight Disease Activating Plant Defense Genes.

pv. () causes bacterial blight and causes sheath blight in rice accounting for >75% of crop losses. Therefore, there is an urgent need to develop strategies for the mitigation of these pathogen infections.

Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype.

Global dysregulation of RNA splicing and imbalanced sphingolipid metabolism has emerged as promoters of cancer cell transformation. Here, we present specific signature of alternative splicing (AS) events of sphingolipid genes for each breast cancer subtype from the TCGA-BRCA dataset. We show that ceramide synthase 2 (CERS2) undergoes a unique cassette exon event specifically in Luminal B subtype tumors.

Infective Endocarditis Guidelines: The Challenges of Adherence-A Survey of Infectious Diseases Clinicians.

Background: Guidelines exist to aid clinicians in managing patients with infective endocarditis (IE), but the degree of adherence with guidelines by Infectious Disease (ID) physicians is largely unknown.

Methods: An electronic survey assessing adherence with selected IE guidelines was emailed to 1409 adult ID physician members of the Infectious Diseases Society of America's Emerging Infections Network.

Results: Five hundred fifty-seven physicians who managed IE responded.

Correction to: Evolution of PVA gels prepared without crosslinking agents as a cell adhesive surface.

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

Ehrlichiosis in a recent kidney transplant recipient: The repellent that did not repel! A case report and literature review of ehrlichiosis in solid organ transplant patients.

Ehrlichiosis has been infrequently reported in immunosuppressed patients such as solid organ transplants (SOT). We report a case of Ehrlichia chaffeensis infection in an immunosuppressed woman four months after deceased donor kidney transplantation. The diagnosis was confirmed by PCR testing in serum, and the patient responded promptly to treatment with doxycycline.

Polydopamine-on-liposomes: stable nanoformulations, uniform coatings and superior antifouling performance.

Polydopamine (PDA), a mussel-inspired synthetic polymer, affords biocompatible and antifouling coatings on a variety of surfaces. However, the traditional protocol of preparing PDA by polymerizing dopamine (DA) under basic conditions yields physically-unstable and non-uniform coatings that are prone to delamination and exhibit compromised antifouling performance in vivo. Here, we show that the high local pH in the vicinity of vesicular self-assemblies formed by a series of acetal-based cationic amphiphiles can be exploited to conveniently polymerise DA under physiological conditions in a gradual manner without requiring any external oxidant.

Cholic Acid-Derived Amphiphile which Combats Gram-Positive Bacteria-Mediated Infections via Disintegration of Lipid Clusters.

Inappropriate and uncontrolled use of antibiotics results in the emergence of antibiotic resistance, thereby threatening the present clinical regimens to treat infectious diseases. Therefore, new antimicrobial agents that can prevent bacteria from developing drug resistance are urgently needed. Selective disruption of bacterial membranes is the most effective strategy for combating microbial infections as accumulation of genetic mutations will not allow for the emergence of drug resistance against these antimicrobials.

Cholic Acid-Peptide Conjugates as Potent Antimicrobials against Interkingdom Polymicrobial Biofilms.

Interkingdom polymicrobial biofilms formed by Gram-positive and pose serious threats of chronic systemic infections due to the absence of any common therapeutic target for their elimination. Herein, we present the structure-activity relationship (SAR) of membrane-targeting cholic acid-peptide conjugates (CAPs) against Gram-positive bacterial and fungal strains. Structure-activity investigations validated by mechanistic studies revealed that valine-glycine dipeptide-derived CAP 3 was the most effective broad-spectrum antimicrobial against and CAP 3 was able to degrade the preformed single-species and polymicrobial biofilms formed by and , and CAP 3-coated materials prevented the formation of biofilms.

Common Variable Immune Deficiency and Associated Complications.

Common variable immunodeficiency disorders refer to a relatively common primary immune deficiency group of diseases that present with infectious and inflammatory complications secondary to defects in antibody production and sometimes in cellular immunity. The disorder often presents in middle age or later with recurrent sinopulmonary infections, bronchiectasis, or a plethora of noninfectious complications such as autoimmune disorders, granulomatous interstitial lung disease, GI diseases, malignancies (including lymphoma), and multisystem granulomatous disease resembling sarcoidosis. Infusion of immunoglobulin by IV or subcutaneous is the mainstay of therapy.

Deciphering the Role of Intramolecular Networking in Cholic Acid-Peptide Conjugates on the Lipopolysaccharide Surface in Combating Gram-Negative Bacterial Infections.

The presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gram-negative bacterial infections highly challenging. Herein, we present the synthesis and antibacterial activities of cholic acid-peptide conjugates (CAPs), demonstrating that valine-glycine dipeptide-derived CAP 3 is the most effective antimicrobial. Molecular dynamics simulations and structural analysis revealed that a precise intramolecular network of CAP 3 is maintained in the form of evolving edges, suggesting intramolecular connectivity.

Oral Delivery of Cholic Acid-Derived Amphiphile Helps in Combating Salmonella-Mediated Gut Infection and Inflammation.

A major impediment to developing effective antimicrobials against Gram-negative bacteria like Salmonella is the ability of the bacteria to develop resistance against existing antibiotics and the inability of the antimicrobials to clear the intracellular bacteria residing in the gastrointestinal tract. As the critical balance of charge and hydrophobicity is required for effective membrane-targeting antimicrobials without causing any toxicity to mammalian cells, herein we report the synthesis and antibacterial properties of cholic acid-derived amphiphiles conjugated with alkyl chains of varied hydrophobicity. Relative to other hydrophobic counterparts, a compound with hexyl chain (6) acted as an effective antimicrobial against different Gram-negative bacteria.

Clathrin-Independent Killing of Intracellular Mycobacteria and Biofilm Disruptions Using Synthetic Antimicrobial Polymers.

Current membrane targeting antimicrobials fail to target mycobacteria due to their hydrophobic membrane structure, ability to form drug-resistant biofilms, and their natural intracellular habitat within the confines of macrophages. In this work, we describe engineering of synthetic antimicrobial polymers (SAMPs) derived from biocompatible polyamides that can target drug-sensitive and drug-resistant mycobacteria with high selectivity. Structure-activity relationship studies revealed that reduced hydrophobicity of cationic pendants induces enhanced and selective permeabilization of mycobacterial membranes.

Stiffness- and wettability-dependent myoblast cell compatibility of transparent poly(vinyl alcohol) hydrogels.

This study reports the in vitro compatibility of muscle cells (C2C12 mouse myoblast cell line) with the transparent poly(vinyl alcohol) (PVA) hydrogels and the results are explained on the basis of surface wettability, crystallinity, and nanoscale elastic stiffness property. Nanoindentation was carried out with a maximum load of 100 μN for all the hydrogel compositions and the properties such as elastic stiffness, hardness and total work done during indentation were computed. The difference in cell viability as well as adhesion of cultured myoblast cells on the investigated hydrogel substrates were discussed in reference to the difference in the nanoscale elastic properties, crystallinity, and surface wettability.

A combined effect of freeze--thaw cycles and polymer concentration on the structure and mechanical properties of transparent PVA gels.

Transparent poly(vinyl alcohol) (PVA) hydrogel films, derived from aqueous solutions of varying concentration, were synthesized by the cyclic freeze-thaw method (0°-37 °C). This study demonstrates a variation in the transparency, degree of crystallinity, wettability, swelling and mechanical properties of the hydrogels as a function of the solution concentration and the number of freeze-thaw cycles for a given average molecular weight (95,000 Da). The study manifests a strong control of the number of freeze-thaw cycles on the structure-property correlations of the synthesized transparent PVA hydrogels, revealing the possibility of obtaining a window of structural and process parameters for the physically cross-linked hydrogels, making them suitable for cell-gel interactions.

Evolution of PVA gels prepared without crosslinking agents as a cell adhesive surface.

Physical parameters (such as crosslinking density, crystallinity and mechanical properties) have been found to largely affect cellular behavior on polymer scaffolds. This study demonstrated that transparent pure Poly (vinyl alcohol) hydrogels prepared via a freeze-thaw method can be made to support cell adhesion by controlling physical parameters such as concentration and the number of freeze-thaw cycles. For a given number of freeze-thaw cycles, (specifically 45), polymer concentration dependent structural and mechanical properties (such as tensile strength and stiffness) were correlated with cell adhesion.

Composition dependent mechanical response of transparent poly(vinyl alcohol) hydrogels.

From biomedical perspective, physically crosslinked poly(vinyl alcohol) hydrogels are excellent materials owing to their biological tissue like nature. Transparent poly(vinyl alcohol) hydrogels, derived from their aqueous solutions, with varying polymer concentrations were synthesized by the simple freeze-thawing method and structure property correlations have been established as a function of concentration. Mechanical stability of the hydrogels has been of prime importance in a number of biomedical applications.

Composition dependent structural modulations in transparent poly(vinyl alcohol) hydrogels.

Transparent and stable Poly(vinyl alcohol) hydrogels were synthesized from polymer aqueous solution without resorting to a mixed solvent such as dimethyl sulfoxide and water. Contrary to the reported methods involving hydrogen bond induced physical crosslinking by repeated freeze-thawing at -20 degrees C, the present process demonstrates the gelation taking place at relatively higher temperature, i.e.