Napthalimide-based nuclease inhibitor: A multifunctional therapeutic material to bolster MRSA uptake by macrophage-like cells and mitigate pathogen adhesion on orthopaedic implant.

The healthcare burden rendered by methicillin-resistant Staphylococcus aureus (MRSA) warrants the development of therapeutics that offer a distinct benefit in the clinics as compared to conventional antibiotics. The present study describes the potential of napthalimide-based synthetic ligands (C1-C3) as inhibitors of the staphylococcal nuclease known as micrococcal nuclease (MNase), a key virulence factor of the pathogen. Amongst the ligands, the most potent MNase inhibitor C1 rendered non-competitive inhibition, reduced MNase turnover number (K) and catalytic efficiency (K/K) with an IC value of ~950 nM.

Inhibition of staphylococcal nuclease by benzimidazole-based Ligand: Implications in DNA-Mediated entrapment and uptake of MRSA by Macrophage-like cells.

The staphylococcal nuclease also referred as micrococcal nuclease (MNase) is a key drug target as the enzyme degrades the neutrophil extracellular trap (NET) and empowers the pathogen to subvert the host innate immune system. To this end, the current study presents a critical evaluation of MNase inhibition rendered by benzimidazole-based ligands (C1 and C2) and probes its therapeutic implications. A nuclease assay indicated that MNase inhibition rendered by C1 and C2 was ∼ 55 % and ∼ 72 %, respectively, at the highest tested concentration of 10 µM.

Anthraquinone-Based Ligands as MNase Inhibitors: Insights from Inhibition Studies and Generation of a Payload Nanocarrier for Potential Anti-MRSA Therapy.

The present study highlights the prospect of an anthraquinone-based ligand (C1) as an inhibitor of micrococcal nuclease (MNase) enzyme secreted by Staphylococcus aureus. MNase inhibition rendered by 5.0 μM C1 was ∼96 % and the ligand could significantly distort the β-sheet conformation present in MNase.

Quinoxaline-based membrane-targeting therapeutic material: Implications in rejuvenating antibiotic and curb MRSA invasion in an in vitro bone cell infection model.

Manifestation of resistance in methicillin-resistant Staphylococcus aureus (MRSA) against multiple antibiotics demands an effective strategy to counter the menace of the pathogen. To address this challenge, the current study explores quinoxaline-based synthetic ligands as an adjuvant material to target MRSA in a combination therapy regimen. Amongst the tested ligands (C1-C4), only C2 was bactericidal against the MRSA strain S.

Urea-Based Ligand as an Efflux Pump Inhibitor: Warhead to Counter Ciprofloxacin Resistance and Inhibit Collagen Adhesion by MRSA.

Methicillin-resistant (MRSA) is a frontline human pathogen in which efflux pump activity confers high levels of antibiotic-resistance and poses a therapeutic challenge in the clinics. The present study illustrates the potential of urea-based ligand as an efflux pump inhibitor (EPI) in order to restore the efficacy of ciprofloxacin (CPX) against MRSA. Among eight structurally varying urea-based ligands, the ligand C8 could significantly inhibit efflux pump activity in the clinical MRSA strain 4s and was superior to the known EPI reserpine.

2-Dodecylmalonic acid-mediated synthesis of mineralized hydroxyapatite amicable for bone cell growth on orthopaedic implant.

The present study illustrates the use of 2-dodecylmalonic acid (MA) as a template in biomineralization-inspired synthesis of hydroxyapatite nanoparticles (HANPs). HANPs synthesized in presence of various concentrations of MA displayed varying particle size and shape. The smallest particle size (22-27 nm) was obtained for MA-HANP synthesized in presence of 37 µM MA.

Probiotic bacteria cell surface-associated protein mineralized hydroxyapatite incorporated in porous scaffold: In vitro evaluation for bone cell growth and differentiation.

There is a high demand for synthesis of biocompatible hydroxyapatite nanoparticle (HANP), which is a key component in bone tissue engineering scaffolds. The present study describes a facile route of HANP synthesis through mineralization of the cell surface-associated protein (CSP) from the human probiotic lactic acid bacteria (LAB) Lactobacillus rhamnosus GG. CSP extract from the LAB (consisting of ~66 kDa, ~47 kDa, ~40 kDa and ~25 kDa protein) was mineralized to yield spindle-shaped HANPs having an average particle length of 371 nm as evidenced in FETEM analysis.

Multifunctional Synthetic Amphiphile for Niche Therapeutic Applications: Mitigation of MRSA Biofilms and Potential in Wound Healing.

The relentless menace of implant- and skin wound-associated infections caused by methicillin-resistant (MRSA) biofilms demands the design of therapeutics that have an edge over conventional antibiotics. The present study reports the potential of pluri-active amphiphiles having a 12-carbon alkyl chain and a salicaldehyde head group (C1) or a napthaldehyde head group (C2) in mitigating wound site- and implant-associated MRSA biofilms and as a topical wound healing agent. The amphiphiles impeded MRSA 100 biofilm formation on collagen both on extraneous addition and on impregnation into collagen and inflicted damage to MRSA cells embedded in collagen matrix infused with simulated wound fluid, with C1 being more potent than C2.

Interplay between Supramolecular and Coordination Interactions in Synthetic Amphiphiles: Triggering Metal Starvation and Anchorage onto MRSA Cell Surface.

The present work highlights the implications of supramolecular interaction and metal coordination on the self-assembly behavior and bactericidal potential of salicaldehyde-(C1) and napthaldehyde-based (C2) amphiphiles against methicillin-resistant (MRSA). LB trough and atomic force microscope (AFM) analysis indicated the propensity of the amphiphiles to form a monolayer as well as spherical aggregates, with the critical micelle concentration (CMC) for C2 (7.0 μM) being lower than C1 (18.

Biocompatible Nanocomposite Tailored to Endure the Gastric Niche Renders Effective in Vitro Elimination of Intestinal Pathogenic Bacteria and Supports Adhesion by Beneficial Bacteria.

Bacteriocins produced by lactic acid bacteria (LAB) are potent therapeutic arsenals for targeting gastrointestinal pathogens and a promising alternative to antibiotics, because of their selective activity and reduced propensity to trigger collateral damage to the beneficial gut microbes. However, proteolytic inactivation in the gastric niche renders bacteriocins ineffective. The present study addresses this challenge and demonstrates that a biocompatible milk protein fraction can be leveraged to generate a robust nanocargo, which renders protection from proteolysis in the gastric milieu and facilitates delivery of the encapsulated bacteriocin pediocin.

Generation of a Hydroxyapatite Nanocarrier through Biomineralization Using Cell-Free Extract of Lactic Acid Bacteria for Antibiofilm Application.

Nanoscale materials hold considerable promise in the mitigation of bacterial infections. In order to exploit nanomaterials as delivery systems in an antibacterial therapeutic paradigm, it is critical to ensure that the generated material is nontoxic. Based on the fundamental principle of biomineralization, we herein report the generation of biocompatible hydroxyapatite nanoparticles (HANPs) in the presence of proteins secreted by the lactic acid bacteria (LAB) MTCC 1325, CRA52, and CRA51.

Al sensing through different turn-on emission signals vis-à-vis two different excitations: Applications in biological and environmental realms.

A rationally designed Schiff base chemosensor (L) could render specific detection of Al ions with two distinct turn-on emission signals, separated by over 100 nm upon excitation at two different wavelengths. The utility of the probe lies in facilitating sensing in 80% aqueous medium with an emission close to 600 nm via an intramolecular charge transfer (ICT) mechanism. The biocompatible and cell permeable probe could readily sense Al in live HeLa cells as well.

Micellar chemotherapeutic platform based on a bifunctional salicaldehyde amphiphile delivers a "combo-effect" for heightened killing of MRSA.

The devastating infections caused by methicillin-resistant Staphylococcus aureus (MRSA) coupled with its high resistance towards antibiotics underscores the need for an effective anti-MRSA therapeutic. The present study illustrates the use of a salicylaldehyde based bactericidal amphiphile (C1) in generating a micellar carrier that renders delivery of therapeutic antibiotics. The inherent membrane-targeting activity of C1 present in the micelle could be leveraged to counter the resistance of MRSA and enhance cellular uptake of the released antibiotics, resulting in effective elimination of the pathogen.

Potential of Pyridine Amphiphiles as Staphylococcal Nuclease Inhibitor.

The present study explores the potential of pyridine-based synthetic amphiphiles C1 and C2 having 4-carbon and 12-carbon hydrophobic tails, respectively, as staphylococcal nuclease inhibitors. UV-visible titration with calf-thymus DNA (CT-DNA) revealed a hypochromic shift in the absorbance bands of C1 and C2, whereas fluorescence titration indicated a reduction in the emission intensity of the monomer bands of the amphiphiles. Interaction of deoxyribonuclease I (DNase 1) and micrococcal nuclease (MNase) with C1 or C2 led to a decrease in the emission intensity of tryptophan at λ=345 nm along with an increase in the monomer emission intensity of C1 and C2 at λ=375 nm for DNase I and excimer emission intensity at λ=470 nm for both DNase I and MNase.

A ratiometric fluorogenic probe for the real-time detection of SO in aqueous medium: application in a cellulose paper based device and potential to sense SO in mitochondria.

A new water soluble and fluorogenic probe (L) that can demonstrate a specific ratiometric detection of a SO derivative (SO) in 100% aqueous medium and live cells has been designed and synthesized. The detection process can be visualized by the naked eye, as the orange-red fluorescence of L turns into a strong blue fluorescence upon interaction with SO. L displayed several beneficial attributes such as detection in complete aqueous medium, extremely fast response time along with high selectivity and sensitivity.

Dual-label flow cytometry-based host cell adhesion assay to ascertain the prospect of probiotic Lactobacillus plantarum in niche-specific antibacterial therapy.

Host cell adhesion assays that provide quantitative insight on the potential of lactic acid bacteria (LAB) to inhibit adhesion of intestinal pathogens can be leveraged for the development of niche-specific anti-adhesion therapy. Herein, we report a dual-colour flow cytometry (FCM) analysis to assess the ability of probiotic Lactobacillus plantarum strains to impede adhesion of Enterococcus faecalis, Listeria monocytogenes and Staphylococcus aureus onto HT-29 cells. FCM in conjunction with a hierarchical cluster analysis could discern the anti-adhesion potential of L.

Amphiphilic Cargo-Loaded Nanocarrier Enhances Antibiotic Uptake and Perturbs Efflux: Effective Synergy for Mitigation of Methicillin-Resistant Staphylococcus aureus.

A pyridinium-amphiphile-loaded poly(lactic-co-glycolic acid) (PLGA) nanocarrier (C1-PNC) was developed as an adjuvant in order to break the resistance and restore the susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC was found to render 8- and 6-fold decreases in the minimum biofilm eradication concentration (MBEC ) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in the case of gentamicin, C1-PNC promotes enhanced cellular uptake of the antibiotic, whereas the propensity of C1-PNC to inhibit efflux pump activity could be leveraged to enhance cellular accumulation of ciprofloxacin, leading to effective killing of MRSA cells.

A Nonbactericidal Zinc-Complexing Ligand as a Biofilm Inhibitor: Structure-Guided Contrasting Effects on Staphylococcus aureus Biofilm.

Zinc-complexing ligands are prospective anti-biofilm agents because of the pivotal role of zinc in the formation of Staphylococcus aureus biofilm. Accordingly, the potential of a thiosemicarbazone (compound C1) and a benzothiazole-based ligand (compound C4) in the prevention of S. aureus biofilm formation was assessed.

A solo fluorogenic probe for the real-time sensing of SO3(2-) and SO4(2-)/HSO4(-) in aqueous medium and live cells by distinct turn-on emission signals.

A judiciously designed fluorogenic probe (L) rendered rapid and differential turn-on responses by exhibiting strong blue fluorescence (λem = 442 nm) for SO3(2-) and greenish-yellow fluorescence (λem = 511 nm) for SO4(2-)/HSO4(-) in 100% aqueous medium and live cells.

Bacteriocin-producing strains of Lactobacillus plantarum inhibit adhesion of Staphylococcus aureus to extracellular matrix: quantitative insight and implications in antibacterial therapy.

In the present study, the adhesion of bacteriocin-producing probiotic strains of Lactobacillus plantarum onto extracellular matrix (ECM) proteins such as collagen and mucin and their potential to prevent pathogen invasion onto the ECM was ascertained. Fluorescence-based in vitro assays indicated that L. plantarum strains CRA21, CRA38 and CRA52 displayed considerable adhesion to ECM molecules, which was comparable to the probiotic Lactobacillus rhamnosus GG.

A zinc complex of a neutral pyridine-based amphiphile: a highly efficient and potentially therapeutic bactericidal material.

The alarming rise in antibiotic-resistant pathogenic bacteria demands a prudent approach in the generation of therapeutic antibacterials. The present study illustrates the development of a potent amphiphilic bactericidal material tailored to leverage interactions with metal-reactive groups (MRGs) present in the bacterial cell surface envelope. Complexation of Zn(ii) with a neutral pyridine-based synthetic amphiphile (C1) generated the cationic C1-Zn, which exhibited manyfold higher membrane-directed bactericidal activity compared to the neutral C1, or the cationic amphiphile bearing two pyridinium head groups (C2).

A sole multi-analyte receptor responds with three distinct fluorescence signals: traffic signal like sensing of Al(3+), Zn(2+) and F(-).

A dialdehyde-based multi-analyte sensor renders distinctive emission spectra for Al(3+), Zn(2+) and F(-) ions. The ligand exhibited different types of interactions with these three different ions resulting in the enhancement of fluorescence intensity at three different wavelengths. All the sensing processes were studied in detail by absorption spectroscopy, emission spectroscopy and (1)H-NMR titration experiment.

Aggregation-Induced Emission Active Metal-Free Chemosensing Platform for Highly Selective Turn-On Sensing and Bioimaging of Pyrophosphate Anion.

We report the synthesis of a metal-free chemosensor for highly selective sensing of pyrophosphate (PPi) anion in physiological medium. The novel phenylbenzimidazole functionalized imine containing chemosensor (L; [2,6-bis(((4-(1H-benzo[d]imidazol-2-yl)phenyl)imino) methyl)-4 methyl phenol]) could sense PPi anion through "turn-on" colorimetric and fluorimetric responses in a very competitive environment. The overall sensing mechanism is based on the aggregation-induced emission (AIE) phenomenon.

A near-infrared emissive Al(3+) sensing platform for specific detection in solution, cells and probing DNase activity.

A new tricarbocyanine-based chemosensor exhibited a dramatic Al(3+)-specific fluorescence turn-on response in the near-infrared (NIR) region. The receptor was found to be highly selective towards Al(3+) over other metal ions in physiological condition. The sensor was non-toxic and could thus be employed as an imaging probe for detecting intracellular Al(3+) in live cells.