Multi-target Strategies Research Articles

Engineered Cell Membrane-Coated Keratin Nanoparticles Attenuated Intervertebral Disc Degeneration by Remodeling the Disc Microenvironment.

Characterized by a cascade of profound changes in nucleus pulposus (NP) cells, extracellular matrix (ECM), and biomechanics, intervertebral disc degeneration is a common multifactorial condition that may lead to various degenerative lumbar disorders. Therapeutic strategies targeting a single factor have shown limited efficacy in treating disc degeneration, and approaches that address multiple pathological ingredients are barely reported. In this study, engineered cell membrane-encapsulated keratin nanoparticles are developed to simultaneously alleviate NP cell senescence and promote ECM remodeling. To achieve this, salivary acid glycoengineered adipose mesenchymal stem cell membranes are used to coat keratin, a core protein for structural support and cellular protection. The synthesized cell membrane-coated keratin nanoparticles (MKNs) effectively protected mitochondrial integrity in NP cells from oxidative stress-induced damage. Moreover, MKNs modulate mitochondrial metabolism and attenuate NP cell senescence. In addition, MKNs activate integrins at the cell membrane and enhance the interactions between NP cells and ECM, resulting in increased ECM anabolism and decreased catabolism. The proposed multi-targeted strategy to block the degenerative cycle inside the disc is efficacious for treating disc degeneration and may have the potential for clinical application.

Integrated Genomics Reveal Potential Resistance Mechanisms of PANoptosis-Associated Genes in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is marked by the proliferation of abnormal myeloid progenitor cells in the bone marrow and blood, leading to low cure rates despite new drug approvals from 2017 to 2018. Current therapies often fail due to the emergence of drug resistance mechanisms, such as those involving anti-apoptotic pathways and immune evasion, highlighting an urgent need for novel approaches to overcome these limitations. Programmed cell death (PCD) is crucial for tissue homeostasis, with PANoptosis-a form of PCD integrating pyroptosis, apoptosis, and necroptosis-recently identified. This process, regulated by the PANoptosome complex, could be key to overcoming AML drug resistance. Targeting multiple PCD pathways simultaneously may prove more effective than single-target therapies. Research suggests that disrupting anti-apoptotic mechanisms, such as those involving Bcl-2, can enhance drug sensitivity in AML. This study hypothesizes that PANoptosis-associated resistance genes (PARGs) play a critical role in AML drug resistance by modulating immune responses and offers a multi-faceted approach to tackle this challenge. Using RNA sequencing data from the Cancer Genome Atlas and Gene Expression Omnibus databases, we performed differential expression analysis to identify significantly dysregulated PARGs in AML. Regression analysis identified prognostic PARGs, bridging a key gap in understanding how these genes contribute to treatment resistance. We then verified their expression in AML cell lines and cell samples treated with cytarabine using RT-qPCR. Hierarchical clustering revealed distinct PARG expression patterns, and functional enrichment analysis highlighted their involvement in immune-related pathways. The combination of bioinformatics and experimental validation underscores how these genes may mediate immune modulation in drug resistance, providing a robust framework for further study. Our findings suggest that PARGs contribute to AML resistance by modulating immune responses and provide potential targets for therapeutic intervention. This study highlights the potential of targeting PARGs to improve treatment outcomes in AML. By analyzing the expression changes of these genes in response to standard clinical treatments, we provide a framework for developing multi-target therapeutic strategies that simultaneously disrupt multiple programmed cell death pathways. Such an approach directly addresses the limitations of current treatments by offering a method to enhance drug sensitivity and mitigate resistance, potentially improving survival rates. Our findings underscore the importance of a comprehensive understanding of PCD mechanisms and pave the way for innovative treatments that could significantly impact AML management.

Accuracy of real-time PCR for the detection of paratuberculosis in actual samples: A systematic review and meta-analysis.

Paratuberculosis, an infectious and chronic ailment that affects ruminants, causes significant annual economic losses to the livestock industry. Early diagnosis and prompt culling are the primary measures for controlling this disease, highlighting the need for accurate and rapid diagnostic methods. This systematic review and meta-analysis aimed to evaluate the efficacy of quantitative PCR (qPCR) in the diagnosis of paratuberculosis. We searched for and selected articles from databases including PubMed, Web of Science, Elsevier ScienceDirect, Wiley-Blackwell, Springerlink, AGRICOLA, and CAB Abstracts, with VETQUADAS (VQ) employed to assess the quality of the literature. Meta-analysis and heterogeneity investigation were conducted using the "Meta4diag" package in "R" software, Meta-Disc 2.0, and Meta-Disc, while the Deeks' test was utilized to detect publication bias. The studies included in the systematic review displayed a moderate level of heterogeneity (I² = 48.6 %) with no significant publication bias (p = 0.998). The pooled sensitivity was determined to be 0.92 [95 % confidence interval [CI], 0.85-0.96], and the specificity was 0.85 [95 % CI, 0.77-0.91], with a summary receiver operating characteristic area under the curve (SROCAUC) of 0.95 [95 % CI, 0.91-0.98]. These findings indicate that the qPCR method has high diagnostic value for identifying paratuberculosis in animals. Subgroup analysis revealed satisfactory stability in these studies; however, the current single-target qPCR detection strategy still has limitations, as it fails to simultaneously ensure both sensitivity and specificity. Future developments should focus on multi-target detection strategies to provide more reliable qPCR testing methods for controlling paratuberculosis.

Advancing COVID-19 Treatment: The Role of Non-covalent Inhibitors Unveiled by Integrated Machine Learning and Network Pharmacology.

The COVID-19 pandemic has necessitated rapid advancements in therapeutic discovery. This study presents an integrated approach combining machine learning (ML) and network pharmacology to identify potential non-covalent inhibitors against pivotal proteins in COVID-19 pathogenesis, specifically B-cell lymphoma 2 (BCL2) and Epidermal Growth Factor Receptor (EGFR). Employing a dataset of 13,107 compounds, ML algorithms such as k-Nearest Neighbors (kNN), Support Vector Machine (SVM), Random Forest (RF), and Naïve Bayes (NB) were utilized for screening and predicting active inhibitors based on molecular features. Molecular docking and molecular dynamics simulations, conducted over a 100 nanosecond period, enhanced the ML-based screening by providing insights into the binding affinities and interaction dynamics with BCL2 and EGFR. Network pharmacology analysis identified these proteins as hub targets within the COVID-19 protein-protein interaction network, highlighting their roles in apoptosis regulation and cellular signaling. The identified inhibitors exhibited strong binding affinities, suggesting potential efficacy in disrupting viral life cycles and impeding disease progression. Comparative analysis with existing literature affirmed the relevance of BCL2 and EGFR in COVID-19 therapy and underscored the novelty of integrating network pharmacology with ML. This multidisciplinary approach establishes a framework for emerging pathogen treatments and advocates for subsequent in vitro and in vivo validation, emphasizing a multi-targeted drug design strategy against viral adaptability. This study's findings are crucial for the ongoing development of therapeutic agents against COVID-19, leveraging computational and network-based strategies.

CRISPR/Cas9-Enhanced CAR-T Cell Therapy for Hematological Malignancies

CRISPR/Cas9 technology has brought revolution to the field of gene editing, offering precise and efficient tools for genetic modifications. One of its most promising applications lies in improving CAR-T cell therapy for treating hematological malignancies. Among approaches to treating blood cancers, CAR-T therapy, which programs T cells to recognize and eliminate cancer cells, has shown some success for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (ALL). However, challenges such as immune evasion, cytokine release syndrome (CRS), neurotoxicity, and limited CAR-T persistence remain significant barriers. CRISPR/Cas9 can optimize CAR-T therapy by precisely inserting CAR genes into specific loci, knocking out inhibitory genes like PD-1 to enhance persistence, and enabling multi-targeting strategies to overcome tumor immune escape. Clinical trials demonstrate the feasibility and potential of CRISPR-edited CAR-T cells, showing improved safety, durability, and efficacy. This study explores the synergistic application of CRISPR/Cas9 in CAR-T therapy, addressing its current limitations and providing a pathway to safer and more effective treatments for hematological malignancies

The Significance of Mono- and Dual-Effective Agents in the Development of New Antifungal Strategies.

Invasive fungal infections (IFIs) pose significant challenges in clinical settings, particularly due to their high morbidity and mortality rates. The rising incidence of these infections, coupled with increasing antifungal resistance, underscores the urgent need for novel therapeutic strategies. Current antifungal drugs target the fungal cell membrane, cell wall, or intracellular components, but resistance mechanisms such as altered drug-target interactions, enhanced efflux, and adaptive cellular responses have diminished their efficacy. Recent research has highlighted the potential of dual inhibitors that simultaneously target multiple pathways or enzymes involved in fungal growth and survival. Combining pharmacophores, such as lanosterol 14α-demethylase (CYP51), heat shock protein 90 (HSP90), histone deacetylase (HDAC), and squalene epoxidase (SE) inhibitors, has led to the development of compounds with enhanced antifungal activity and reduced resistance. This dual-target approach, along with novel chemical scaffolds, not only represents a promising strategy for combating antifungal resistance but is also being utilized in the development of anticancer agents. This review explores the development of new antifungal agents that employ mono-, dual-, or multi-target strategies to combat IFIs. We discuss emerging antifungal targets, resistance mechanisms, and innovative therapeutic approaches that offer hope in managing these challenging infections.

Clinical management of chronic wound infections: The battle against biofilm.

Bacteria constitute the most abundant life form on earth, of which the majority exist in a protective biofilm state. Since the 1980s, we have learned much about the role of biofilm in human chronic infections, with associated global healthcare costs recently estimated at ~$386 billion. Chronic wound infection is a prominent biofilm-induced condition that is characterised by persistent inflammation and associated host tissue destruction, and clinical signs that are distinct from signs of acute wound infection. Biofilm also enables greater tolerance to antimicrobial agents in chronic wound infections compared with acute wound infections. Given the difficulty in eliminating wound biofilm, a multi-targeted strategy (namely biofilm-based wound care) involving debridement and antimicrobial therapies were introduced and have been practiced since the early 2000s. More recently, acknowledgement of the speed at which biofilm can develop and hence quickly interfere with wound healing has highlighted the need for an early anti-biofilm strategy to combat biofilm before it takes control and prevents wound healing. This strategy, referred to as wound hygiene, involves multiple tools in combination (debridement, cleansing, and antimicrobial dressings) to maximise success in biofilm removal and encourage wound healing. This review is intended to highlight the issues and challenges associated with biofilm-induced chronic infections, and specifically address the challenges in chronic wound management, and tools required to combat biofilm and encourage wound healing.

Understanding Why Metabolic-Dysfunction-Associated Steatohepatitis Lags Behind Hepatitis C in Therapeutic Development and Treatment Advances

Therapeutic development for metabolic-dysfunction-associated steatohepatitis (MASH) trails behind the success seen in hepatitis C virus (HCV) management. HCV, characterized by a viral etiology, benefits from direct-acting antivirals (DAAs) targeting viral proteins, achieving cure rates exceeding 90%. In contrast, MASH involves complex metabolic, genetic, and environmental factors, presenting challenges for drug development. Non-invasive diagnostics like ultrasound, FibroScan, and serum biomarkers, while increasingly used, lack the diagnostic accuracy of liver biopsy, the current gold standard. This review evaluates therapies for MASH, including resmetirom (Rezdiffra) and combinations like pioglitazone and vitamin E, which show potential but offer modest improvements due to MASH’s heterogeneity. The limited efficacy of these treatments highlights the need for multi-targeted strategies addressing metabolic and fibrotic components. Drawing parallels to HCV’s success, this review emphasizes advancing diagnostics and therapies for MASH. Developing effective, patient-specific therapies is crucial to closing the gap between MASH and better-managed liver diseases, optimizing care for this growing health challenge.

Investigating antibacterial and anti-inflammatory properties of synthetic curcuminoids.

The concept of intratumoral microbiota is gaining attention in current research. Tumor-associated microbiota can activate oncogenic signaling pathways such as NF-κB, thereby promoting tumor development and progression. Numerous studies have demonstrated that curcumin and its analogs possess strong antitumor effects by targeting the NF-κB signaling pathway, along with potent antibacterial properties. In this study, we tested the antibacterial activity of two curcuminoids, Py-cPen and V-cPen, against the Gram-negative bacterial strains Pseudomonas aeruginosa and Escherichia coli and the Gram-positive bacterial strain Streptococcus aureus using in vitro assays and fluorescent microscopy. We observed that both Py-cPen and V-cPen reduced NF-κB activation upon lipopolysacharide (LPS) challenge in cell assays. In addition, our findings indicate that Py-cPen and V-cPen interact with LPS, as demonstrated by transmission electron microscopy and confirmed using in silico analyses, thereby modulating LPS activity. Overall, our data indicate that Py-cPen and V-cPen exhibit strong antibacterial and antiinflammatory properties, suggesting their potential as candidates for new multitarget therapeutic strategies.

Computer-Aided Identification and Design of Ligands for Multi-Targeting Inhibition of a Molecular Acute Myeloid Leukemia Network.

Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3-8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target-drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML.

Azole Combinations and Multi-Targeting Drugs That Synergistically Inhibit Candidozyma auris.

Limited antifungal treatment options and drug resistance require innovative approaches to effectively combat fungal infections. Combination therapy is a promising strategy that addresses these pressing issues by concurrently targeting multiple cellular sites. The drug targets usually selected for combination therapy are from different cellular pathways with the goals of increasing treatment options and reducing development of resistance. However, some circumstances can prevent the implementation of combination therapy in clinical practice. These could include the increased risk of adverse effects, drug interactions, and even the promotion of drug resistance. Furthermore, robust clinical evidence supporting the superiority of combination therapy over monotherapy is limited and underscores the need for further research. Despite these challenges, synergies detected with different antifungal classes, such as the azoles and echinocandins, suggest that treatment strategies can be optimized by better understanding the underlying mechanisms. This review provides an overview of multi-targeting combination strategies with a primary focus on Candidozyma auris infections.

Enhanced Recognition Memory through Dual Modulation of Brain Carbonic Anhydrases and Cholinesterases.

This study introduces a novel multitargeting strategy that combines carbonic anhydrase (CA) activators and cholinesterase (ChE) inhibitors to enhance cognitive functions. A series of tacrine-based derivatives with amine/amino acid moieties were synthesized and evaluated for their dual activity on brain CA isoforms and ChEs (AChE and BChE). Several derivatives, notably compounds 26, 30, 34, and 40, demonstrated potent CA activation, particularly of hCA II and VII, and strong ChE inhibition with subnanomolar to low nanomolar IC50 values. In vivo studies using a mouse model of social recognition memory showed that these derivatives significantly improved memory consolidation at doses 10-100 times lower than the reference compounds (either alone or in combination). Molecular modeling and ADMET predictions elucidated the compound binding modes and confirmed favorable pharmacokinetic and safety profiles. The findings suggest that dual modulation of CA and ChE activities is a promising strategy for treating cognitive deficits associated with neurodegenerative and psychiatric disorders.

Forecasting the Pharmacological Mechanisms of Plumbago zeylanica and Solanum xanthocarpum in Diabetic Retinopathy Treatment: A Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation Study.

(1) Background: Diabetic retinopathy (DR) is a major complication of diabetes, marked by abnormal angiogenesis, microaneurysms, and retinal hemorrhages. Traditional Ayurvedic medicine advocates multi-target strategies for DR management. However, the mechanisms by which Solanum xanthocarpum (SX) and Plumbago zeylanica (PZ) exert therapeutic effects are not well understood; (2) Methods: To investigate these mechanisms, we employed network pharmacology and molecular docking techniques. Phytochemicals from SX and PZ were identified using the IMPPAT database and Swiss Target Prediction tool. DR-related protein targets were sourced from the GeneCards database, and common targets were identified through Venn diagram analysis. STRING and Cytoscape were used to construct and analyze protein-protein interaction networks. Pathway enrichment was performed with Gene Ontology and KEGG databases; (3) Results: We identified 28 active phytoconstituents, targeting proteins such as EGFR, SRC, STAT3, AKT1, and HSP90AA1. Molecular docking and dynamics simulations confirmed the strong binding affinities of these compounds to their targets; (4) Conclusions: The study highlights the multi-target activity of SX and PZ, particularly in pathways related to EGFR tyrosine kinase inhibitor resistance and PI3K-AKT signaling. These findings provide valuable insights into their therapeutic potential for DR, suggesting the effective modulation of key molecular pathways involved in the disease.

Phosphorus Dendrimers Co-deliver Fibronectin and Edaravone for Combined Ischemic Stroke Treatment via Cooperative Modulation of Microglia/Neurons and Vascular Regeneration.

The development of new multi-target combination treatment strategies to tackle ischemic stroke (IS) remains to be challenging. Herein, a proof-of-concept demonstration of an advanced nanomedicine formulation composed of macrophage membrane (MM)-camouflaged phosphorous dendrimer (termed as AK137)/fibronectin (FN) nanocomplexes (NCs) loaded with antioxidant edaravone (EDV) to modulate both microglia and neurons for effective IS therapy is showcased. The created MM@AK137-FN/EDV (M@A-F/E) NCs with a mean size of 260nm possess good colloidal stability, sustained EDV release kinetics, and desired cytocompatibility. By virtue of MM decoration, the M@A-F/E NCs can cross blood-brain barrier, act on microglia to exert the anti-inflammatory (AK137 and FN) and antioxidative (FN and EDV) effects in vitro for oxidative stress alleviation, microglia M2 polarization, and reduction of pro-inflammatory cytokine secretion, and act on neuron cells to be anti-apoptotic. In a transient middle cerebral artery occlusion rat model, the developed M@A-F/E NCs can exert enhanced antioxidant/anti-inflammatory/anti-apoptotic therapeutic effects to comprehensively regulate the brain microenvironment and promote vascular regeneration to collaboratively restore the blood flow after ischemia-reperfusion. The designed MM-coated NCs composed of all-active ingredients of phosphorous dendrimers, FN, and EDV that can fully regulate the brain inflammatory microenvironment may expand their application scope in other neurodegenerative diseases.

Molecular Transformers: Adaptive Multitarget Ligands for Esterase-Induced Transition from Analgesics to Anesthetics.

Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Nav1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABAA) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25's dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.

Santalum album L. alleviates cardiac function injury in heart failure by synergistically inhibiting inflammation, oxidative stress and apoptosis through multiple components

BackgroundHeart failure (HF) is a complex cardiovascular syndrome with high mortality. Santalum album L. (SAL) is a traditional Chinese medicine broadly applied for various diseases treatment including HF. However, the potential active compounds and molecular mechanisms of SAL in HF treatment are not well understood. MethodsThe active compounds and possible mechanisms of action of SAL were analyzed and validated by a systems pharmacology framework and an ISO-induced mouse HF model.ResultsWe initially confirmed that SAL alleviates heart damage in ISO-induced HF model. A total of 17 potentially active components in SAL were identified, with Luteolin (Lut) and Syringaldehyde (SYD) in SAL been identified as the most effective combination through probabilistic ensemble aggregation (PEA) analysis. These compounds, individually and in their combination (COMB), showed significant therapeutic effects on HF by targeting multiple pathways involved in anti-oxidation, anti-inflammation, and anti-apoptosis. The active ingredients in SAL effectively suppressed inflammatory mediators and pro-apoptotic proteins while enhancing the expression of anti-apoptotic factors and antioxidant markers. Furthermore, the synergistic effects of SAL on YAP and PI3K-AKT signaling pathways were further elucidated.ConclusionsMechanistically, the anti-HF effect of SAL is responsible for the synergistic effect of anti-inflammation, antioxidation and anti-apoptosis, delineating a multi-targeted therapeutic strategy for HF.Graphical

Multi-Target In-Silico modeling strategies to discover novel angiotensin converting enzyme and neprilysin dual inhibitors

Cardiovascular diseases, including heart failure, stroke, and hypertension, affect 608 million people worldwide and cause 32% of deaths. Combination therapy is required in 60% of patients, involving concurrent Renin–Angiotensin–Aldosterone-System (RAAS) and Neprilysin inhibition. This study introduces a novel multi-target in-silico modeling technique (mt-QSAR) to evaluate the inhibitory potential against Neprilysin and Angiotensin-converting enzymes. Using both linear (GA-LDA) and non-linear (RF) algorithms, mt-QSAR classification models were developed using 983 chemicals to predict inhibitory effects on Neprilysin and Angiotensin-converting enzymes. The Box-Jenkins method, feature selection method, and machine learning algorithms were employed to obtain the most predictive model with ~ 90% overall accuracy. Additionally, the study employed virtual screening of designed scaffolds (Chalcone and its analogues, 1,3-Thiazole, 1,3,4-Thiadiazole) applying developed mt-QSAR models and molecular docking. The identified virtual hits underwent successive filtration steps, incorporating assessments of drug-likeness, ADMET profiles, and synthetic accessibility tools. Finally, Molecular dynamic simulations were then used to identify and rank the most favourable compounds. The data acquired from this study may provide crucial direction for the identification of new multi-targeted cardiovascular inhibitors.

In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells.

Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.

Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria.

Addressing the global challenge of bacterial resistance demands innovative approaches, among which multitargeting is a widely used strategy. Current strategies of multitargeting, typically achieved through drug combinations or single agents inherently aiming at multiple targets, face challenges such as stringent pharmacokinetic and pharmacodynamic requirements and cytotoxicity concerns. In this report, we propose a bacterial-specific global disruption approach as a vastly expanded multitargeting strategy that effectively disrupts bacterial subcellular organization. This effect is achieved through a pioneering chemical design of ligand-receptor interaction-induced aggregation of small molecules, i.e., DNA-induced aggregation of a diarginine peptidomimetic within bacterial cells. These intracellular aggregates display affinity toward various proteins and thus substantially interfere with essential bacterial functions and rupture bacterial cell membranes in an "inside-out" manner, leading to robust antibacterial activities and suppression of drug resistance. Additionally, biochemical analysis of macromolecule binding affinity, cytoplasmic localization patterns, and bacterial stress responses suggests that this bacterial-specific intracellular aggregation mechanism is fundamentally different from nonselective classic DNA or membrane binding mechanisms. These mechanistic distinctions, along with the peptidomimetic's selective permeation of bacterial membranes, contribute to its favorable biocompatibility and pharmacokinetic properties, enabling its in vivo antimicrobial efficacy in several animal models, including mice-based superficial wound models, subcutaneous abscess models, and septicemia infection models. These results highlight the great promise of ligand-receptor interaction-induced intracellular aggregation in achieving a globally disruptive multitargeting effect, thereby offering potential applications in the treatment of malignant cells, including pathogens, tumor cells, and infected tissues.

An Insight into Mesoporous Silica Nanoparticles: Ray of Hope for Cancer Management

Abstract: Cancer is one of the fatal diseases leading to a high mortality rate. The conventional formulations available for the treatment of cancer are associated with several drawbacks. The major ones are increased side effects due to improper tumor selectivity, metastasis of cancer cells and development of multi-drug resistance to available chemotherapeutic drugs. The development of nanobased formulations for the treatment of cancer has been found to be beneficial up to a great extent. Mesoporous Silica nanoparticles are one of the nanotechnology-based formulations that could overcome major disadvantages associated with conventional therapy, such as metastasis, multi-drug resistance and side effects to normal cells. MSN-based nanoformulations could provide dual therapeutic effects against cancer cells. Due to their small size and large surface, which could be functionalized by using different targeting and therapeutic moieties, they provide targeted and enhanced drug delivery. This review highlights Mesoporous silica nanoparticles along with their properties, drug encapsulation and various applications in drug delivery, such as multi-targeting strategy, and multimodal combined therapy by using ultrasound, photodynamic etc. In the future, MSN-based nanomedicines could be used to develop other innovative strategies for cancer treatment.