Modulating polybasic character of galactose-based glycosylated antitumor ether lipids for enhanced cytotoxic response.

We describe the structure-activity relationship studies of galactose-based glycosylated antitumor ether lipids (GAELs) by installing amine groups at different positions of galactose and the glycerol backbone. Different dibasic and tribasic analogues of -GAELs were synthesized and tested against a panel of human epithelial cancer cell lines. A β-anomeric triamino galactose scaffold, was the most active compound of the series and displayed CC in the range of 2.

Enhancing outer membrane permeability of tetracycline antibiotics in using TOB-CIP conjugates.

is an opportunistic critical 'priority 1' Gram-negative bacterium that poses a severe threat to public healthcare due to rising antibiotic resistance. Particularly, low membrane permeability and overexpression of efflux pumps in lead to intrinsic resistance that compromises the antibacterial activity of antibiotics. The broad-spectrum antibiotics class, tetracyclines, are rarely used to treat infections.

Exploring Structure-Activity Relationships of Niclosamide-Based Colistin Potentiators in Colistin-Resistant Gram-Negative Bacteria.

Colistin is primarily used as a last resort antibiotic against highly resistant Gram-negative bacteria (GNB). Rising rates of colistin resistance, however, may limit future use of this agent. The anthelmintic drug niclosamide has been shown to enhance colistin activity in combination therapy, but a detailed structure-activity relationship (SAR) for niclosamide against GNB has yet to be studied.

Exploring Antibiotic-Potentiating Effects of Tobramycin-Deferiprone Conjugates in .

Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including . To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB).

Guanidinylated Amphiphilic Tobramycin Derivatives Synergize with β-Lactam/β-Lactamase Inhibitor Combinations against .

Carbapenem-resistant () was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid dissemination of β-lactamases in , β-lactam (BL) antibiotics are used in conjunction with β-lactamase inhibitors (BLI). The effectiveness of the BL/BLI combination could be further enhanced with the inclusion of an outer membrane (OM) permeabilizer, such as aminoglycosides and aminoglycoside-based adjuvants.

Trimeric Tobramycin/Nebramine Synergizes β-Lactam Antibiotics against .

β-Lactam antibiotics remain one of the most effective therapeutics to treat infections caused by Gram-negative bacteria (GNB). However, since ancient times, bacteria have developed multiple resistance mechanisms toward this class of antibiotics including overexpression of β-lactamases, suppression of porins, outer membrane impermeability, overexpression of efflux pumps, and target modifications. To cope with these challenges and to extend the lifetime of existing β-lactam antibiotics, β-lactamase inhibitors are combined with β-lactam antibiotics to prevent antibiotic inactivation by β-lactamases.

Amphiphilic tribasic galactosamines potentiate rifampicin in Gram-negative bacteria at low Mg/Caconcentrations.

Many antibiotics specific to Gram-positive bacteria like rifampicin (RIF) are inactive in Gram-negative bacteria because of outer membrane (OM) impermeability. Enhancing the OM permeability of these antibiotics with the help of OM perturbants is a promising strategy to develop new agents against Gram-negative bacteria. Here we report the synthesis and biological properties of amphiphilic tribasic galactosamines as potential RIF potentiators.

Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and β-Lactam Antibiotics against Multidrug-Resistant .

According to the World Health Organization, antibiotic resistance is a global health threat. Of particular importance are infections caused by multidrug-resistant Gram-negative bacteria including , , , and for which limited treatment options exist. Multiple and simultaneously occurring resistance mechanisms including outer membrane impermeability, overexpression of efflux pumps, antibiotic-modifying enzymes, and modification of genes and antibiotic targets have made antibiotic drug development more difficult against these pathogens.

Guanidinylated Polymyxins as Outer Membrane Permeabilizers Capable of Potentiating Rifampicin, Erythromycin, Ceftazidime and Aztreonam against Gram-Negative Bacteria.

Polymyxins are considered a last-line treatment against infections caused by multidrug-resistant (MDR) Gram-negative bacteria. In addition to their use as a potent antibiotic, polymyxins have also been utilized as outer membrane (OM) permeabilizers, capable of augmenting the activity of a partner antibiotic. Several polymyxin derivatives have been developed accordingly, with the objective of mitigating associated nephrotoxicity.

The Potential of Novel Lipid Agents for the Treatment of Chemotherapy-Resistant Human Epithelial Ovarian Cancer.

Recurrent epithelial ovarian cancer (EOC) coincident with chemotherapy resistance remains the main contributor to patient mortality. There is an ongoing investigation to enhance patient progression-free and overall survival with novel chemotherapeutic delivery, such as the utilization of antiangiogenic medications, PARP inhibitors, or immune modulators. Our preclinical studies highlight a novel tool to combat chemotherapy-resistant human EOC.

Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin.

Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β-homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes.

Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo.

Chemotherapy resistant high grade serous ovarian cancer remains a clinically intractable disease with a high rate of mortality. We tested a novel glycosylated antitumor ether lipid called l-Rham to assess the in vitro and in vivo efficacy on high grade serous ovarian cancer cell lines and patient samples. l-Rham effectively kills high grade serous ovarian cancer cells grown as 2D or 3D cultures in a dose and time dependent manner.

LIGHT: A Church-Based Curriculum for Training African American Lay Health Workers to Support Advance Care Planning and End-of-Life Decision-Making.

African Americans with life-limiting illnesses experience significant health inequities. Lay health workers (LHWs) may help overcome existing challenges of communicating with African Americans about advance care planning (ACP) and end-of-life decision-making. Church-based LHWs have some advantages over other LHWs but no curriculum exists to fully prepare them.

Faith Beliefs of African American Church Leaders Are Aligned With the Principles of Palliative and Hospice Care: A Community-Based Assessment and Intervention.

Background: African American (AA) church leaders often advise AAs with serious and life-limiting illnesses (LLIs).

Objectives: 1) determine beliefs of AA church leaders about palliative care and hospice care (PCHC), 2) assess association of participants' attitude about encouraging a loved one to learn about PCHC with whether PC or HC is consistent with faith beliefs and can reduce suffering and bring comfort, and 3) evaluate an interactive, educational intervention.

Design: prospective, one group, pre and post assessment of beliefs and attitudes Settings/Subjects: 100 church leaders from 3 AA Churches and one AA Church Consortium.

Syntheses of L-Rhamnose-Linked Amino Glycerolipids and Their Cytotoxic Activities against Human Cancer Cells.

A major impediment to successful cancer treatment is the inability of clinically available drugs to kill drug-resistant cancer cells. We recently identified metabolically stable L-glucosamine-based glycosylated antitumor ether lipids (GAELs) that were cytotoxic to chemotherapy-resistant cancer cells. In the absence of commercially available L-glucosamine, many steps were needed to synthesize the compound and the overall yield was poor.

Potentiation of β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin-cyclam conjugates.

Objectives: To develop a multifunctional adjuvant molecule that can rescue β-lactam antibiotics and β-lactam/β-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clinical isolates.

Methods: Preparation of adjuvant was guided by structure-activity relationships, following standard protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold dilution assays.

Heterodimeric Rifampicin-Tobramycin conjugates break intrinsic resistance of Pseudomonas aeruginosa to doxycycline and chloramphenicol in vitro and in a Galleria mellonella in vivo model.

Intrinsic resistance in Pseudomonas aeruginosa, defined by chromosomally encoded low outer membrane permeability and constitutively over-expressed efflux pumps, is a major reason why the pathogen is refractory to many antibiotics. Herein, we report that heterodimeric rifampicin-tobramycin conjugates break this intrinsic resistance and sensitize multidrug and extensively drug-resistant P. aeruginosa to doxycycline and chloramphenicol in vitro and in vivo.

Engaging the African American Church to Improve Communication About Palliative Care and Hospice: Lessons From a Multilevel Approach.

Background: As the spiritual family for many African Americans, the church presents an opportunity to improve communication about palliative care and hospice (PCH). However, sustainable change in church-based, practices related to PCH requires a compreshensive, multilevel approach.

Objectives: Our primary goal was to encourage churches to embrace palliative care and hospice as acceptable alternatives for end-of-life care by creating venues to improve communications about PCH.

Short Proline-Rich Lipopeptide Potentiates Minocycline and Rifampin against Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa.

A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C) possess optimal antibacterial activity relative to others with shorter lipid components. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Out of 16 prepared SPRLPs, C-PRP was found to significantly potentiate the antibiotics minocycline and rifampin against multidrug- and extensively drug-resistant (MDR/XDR) clinical isolates.

Amphiphilic Modulation of Glycosylated Antitumor Ether Lipids Results in a Potent Triamino Scaffold against Epithelial Cancer Cell Lines and BT474 Cancer Stem Cells.

The problems of resistance to apoptosis-inducing drugs, recurrence, and metastases that have bedeviled cancer treatment have been attributed to the presence of cancer stem cells (CSCs) in tumors, and there is currently no clinically indicated drug for their eradication. We previously reported that glycosylated antitumor ether lipids (GAELs) display potent activity against CSCs. Here, we show that by carefully modulating the amphiphilic nature of a monoamine-based GAEL, we can generate a potent triamino scaffold that is active against a panel of hard-to-kill epithelial cancer cell lines (including triple-negative breast) and BT474 CSCs.

Novel glycolipid agents for killing cisplatin-resistant human epithelial ovarian cancer cells.

Background: Chemotherapy resistance is one of the major factors contributing to mortality from human epithelial ovarian cancer (EOC). Identifying drugs that can effectively kill chemotherapy-resistant EOC cells would be a major advance in reducing mortality. Glycosylated antitumour ether lipids (GAELs) are synthetic glycolipids that are cytotoxic to a wide range of cancer cells.

Replacing d-Glucosamine with Its l-Enantiomer in Glycosylated Antitumor Ether Lipids (GAELs) Retains Cytotoxic Effects against Epithelial Cancer Cells and Cancer Stem Cells.

We describe metabolically inert l-glucosamine-based glycosylated antitumor ether lipids (L-GAELs) that retain the cytotoxic effects of the D-GAELs including the ability to kill BT-474 breast cancer stem cells (CSCs). When compared to adriamycin, cisplatin, and the anti-CSC agent salinomycin, L-GAELs display superior activity to kill cancer stem cells (CSCs). Mode of action studies indicate that L-GAELs like the D-GAELs kill cells via an apoptosis-independent mechanism that was not due to membranolytic effects.

Ultrashort cationic lipopeptides and lipopeptoids: Evaluation and mechanistic insights against epithelial cancer cells.

Peptides present an attractive scaffold for the development of new anticancer lead agents due to their accessibility and ease of modification. Synthetic ultrashort cationic lipopeptides, with four amino acids or less conjugated to a fatty acid, were developed to retain the biological activity of longer peptides in a smaller molecular size. Herein, we report the activity of amphiphilic lipotripeptides, lipotripeptoids and lipotetrapeptides against breast (MDA-MB-231, JIMT-1), prostate (DU145) and pancreas (MiaPaCa2) epithelial cancer cell lines.

Synthesis and antiproliferative properties of a new ceramide analog of varacin.

A benzopentasulfane was synthesized in 8 steps with a ceramide attached through an amide bond to the 7-position of the heterocycle structure. The anticancer activity of this synthetic ceramide-benzopolysulfane drug conjugate was analyzed against five human cancer cell lines MDA-MB-231 (breast), DU145 (prostate), MIA PaCa-2 (pancreas), HeLa (cervix), and U251 (glioblastoma). The ceramide-benzopolysulfane conjugate had IC50 values ranging from 10 to >20 μM with complete cell killing at 12.

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids.

Glycosylated antitumor ether lipids (GAELs) kill cancer cells and cancer stem cells via a novel, apoptosis-independent mechanism. In contrast, chlorambucil, a drug in clinical use for the treatment of chronic lymphocytic leukemia reacts with nucleophiles within the major groove of DNA, leading to apoptosis. We hypothesized that hybrid molecules that combine apoptosis-dependent and apoptosis-independent mode of actions in a single molecule may lead to enhanced antitumor activity.