Search Results (147)

Drug resistance represents one of the most critical challenges in modern medicine, undermining the efficacy of therapies across both bacterial infections and cancer. Although these conditions arise in fundamentally distinct biological systems, they are governed by shared evolutionary pressures that drive the emergence and selection of resistant populations. This narrative review provides an integrative, cross-disciplinary perspective on drug resistance, focusing on bacteria and cancer and emphasizing the shared evolutionary and molecular mechanisms underlying treatment failure in both domains. Key resistance strategies include efflux-mediated drug export, target modification, enzymatic drug inactivation, metabolic reprogramming, epigenetic and transcriptional plasticity, and protection conferred by specialized microenvironments. These processes are further reinforced by phenotypic heterogeneity, including bacterial persister cells and cancer stem-like cells, which contribute to recurrence and multidrug resistance. Collectively, these parallels define drug resistance as a convergent evolutionary phenomenon driven by adaptability under selective pressure. Recognizing these shared mechanisms reveals important translational opportunities for therapeutic intervention. Strategies such as combination therapy, drug repurposing, nanotechnology-enabled delivery systems, and host-directed approaches offer promising avenues to prevent, delay, or overcome resistance. By integrating insights from microbiology and oncology, this review proposes a unified framework for resistance biology and highlights the potential of cross-disciplinary strategies to improve treatment durability and clinical outcomes. Full article

Antibiotics primarily exert their effect on planktonic microbial states, limiting their ability to eradicate biofilms commonly seen in chronic infections. This is because the minimal inhibitory concentration of antibiotics needed to kill microbes in biofilms can be up to 1000 times greater than when microbes are in their planktonic state. Yet up to 70% of all chronic infections are associated with a biofilm component. Consequently, novel therapeutics are needed to aid in the treatment of chronic biofilm infections. One such approach is to repurpose drugs that have demonstrated safety for non-infectious clinical indications. The main advantage of this approach is that the agents have already been shown to be safe for human administration, which can expedite clinical trial development of agents for biofilm infections. Unfortunately, most clinicians are unaware of the antimicrobial properties of some commonly used drugs. Thus, the aim of this Perspective was to discuss the potential of four drugs that have theoretical promise as adjuvants in the treatment of chronic biofilm infections. This was accomplished by providing detailed discussion of each agent with respect to current clinical use, potential mechanisms of antimicrobial activity, and present data to support use as adjuvant biofilm agents. Full article

Background/Objectives: The rapid emergence of antimicrobial resistance (AMR) is driven not only by antibiotic selective pressure but also by bacterial adaptive responses that enhance genetic diversification under stress. The SOS response, regulated by the RecA-LexA axis, plays a central role in coordinating DNA repair, mutagenesis, and phenotypic adaptation. Targeting this pathway represents a promising strategy to limit bacterial adaptability without directly affecting viability. This study aimed to evaluate benzoxaborole-based compounds as potential inhibitors of the LexA regulatory pathway. Methods: A drug repurposing approach was employed to investigate the benzoxaborole scaffold and the clinically approved derivatives tavaborole and crisaborole. Biochemical assays were used to assess LexA autocleavage in a RecA-dependent co-protease system. Molecular docking analyses were performed to evaluate compound binding within the LexA catalytic site. Microbiological assays were conducted to examine the effects on antibiotic-induced filamentation and biofilm formation under different growth conditions. Results: Selected benzoxaboroles inhibited LexA autocleavage, with tavaborole showing the strongest inhibitory profile in the biochemical assay. Docking analyses supported these findings, indicating stable binding within the LexA catalytic site near the catalytic serine residue. At the cellular level, tavaborole and benzoxaborole significantly reduced levofloxacin-induced filamentation at sub-inhibitory concentrations. Both compounds also decreased biofilm formation under nutrient-limited conditions, while no significant effects were observed on preformed biofilms. Crisaborole showed limited cellular activity despite measurable biochemical effects. Conclusions: These findings identify benzoxaboroles as modulators of the LexA-dependent SOS response and support the potential repurposing of clinically approved compounds as adjuvants to limit bacterial adaptive responses associated with antimicrobial resistance. Full article

Superficial mycoses (dermatomycoses) are a growing healthcare concern due to antifungal resistance, particularly among aging and immunocompromised populations. Multiple efforts are underway to develop novel antifungals, including discovering new compounds with known or new mechanisms of action, extending indications or repurposing existing medications, and utilizing vaccination and nanotechnology platforms. Herein, we conducted a scoping review of novel antifungals for the treatment of dermatomycoses. An electronic literature search restricted to the past 10 years was performed in January 2026 using PubMed and Embase (Ovid). Olorofim and ME1111 represent novel drug classes that target intracellular metabolism. New agents belonging to the azole class demonstrate reduced drug–drug interactions (oteseconazole), a broader antifungal spectrum (voriconazole), and reduced pharmacokinetic complexity (fosravuconazole, super-bioavailable itraconazole). Other investigational compounds include allicin, a phytocompound, and miltefosine, a repurposed antileishmanial drug. Based on our current understanding of dermatophyte immunity, antimicrobial peptides and vaccines targeting virulence factors (e.g., subtilisins) represent novel strategies. Nanotechnology platforms also show promise in introducing new antifungal agents (e.g., metal nanoparticles, nitric oxide-releasing nanoparticles), as well as developing topical formulations to enhance the bioavailability and safety profiles of existing antifungals (amphotericin B, ketoconazole, voriconazole). Full article

Radiotherapy is the central component in non-small cell lung cancer (NSCLC) treatment. Nonetheless, its therapeutic effectiveness is frequently compromised by adaptive engagement of prosurvival signaling pathways that foster radioresistance. STAT3 functions as the central signaling node that orchestrates cellular survival responses following radiation exposure. This study investigated whether nitroxoline, a clinically approved antimicrobial agent with STAT3-inhibitory activity, enhances radiosensitivity of NSCLC cells and how these effects are mechanistically regulated. We examined the combined effects of nitroxoline and radiation on cell viability and associated signaling pathways in NSCLC cells. Nitroxoline significantly enhanced radiation-induced cytotoxicity and suppressed clonogenic survival compared with radiation alone. Irradiation increased STAT3, AKT, and mTOR phosphorylation, whereas nitroxoline effectively suppressed the basal and radiation-induced activation of these pathways. The combination treatment markedly augmented radiation-induced apoptosis, as demonstrated by increased p53 expression and enhanced PARP and caspase-3 cleavage. Additionally, nitroxoline amplified radiation-induced DNA damage signaling, resulting in pronounced γ-H2AX and DNA-PKcs accumulation. Nitroxoline enhanced NSCLC cell radiosensitivity by suppressing STAT3–AKT–mTOR survival signaling, promoting apoptosis, and amplifying radiation-induced DNA damage, indicating the potential of repurposing nitroxoline as a radiosensitizer to improve radiotherapy outcomes in patients with NSCLC. Full article

Background/Objectives: Antimicrobial peptides (AMPs) represent a promising class of therapeutics with diverse biological functions, including antibacterial, anti-fungal, anti-parasitic and anti-tumoral activities. Previous works demonstrated the successful repurposing of the two synthetic AMPs 19-2.5 and 19-4LF for cutaneous leishmaniasis, when the compounds were administered in solution on skin lesions caused by Leishmania major in a BALB/c mouse model. In this research project, we assessed the activity of 19-4LF, 19-2.5, and their hybrid 19-2.5LF derivative when formulated as a cream for topical administration in the same animal model. Methods: The peptides were formulated in DAC cream and applied to the wound of BALB/C mice for 30 days. Lesion progression was monitored using a digital caliper. Parasite burden was measured by qPCR. Parasite viability was assessed using MTT and microscopy imaging assays. Results: The three peptides in cream formulation succeeded in reducing the skin lesion. Peptide 19-4LF was the most potent, followed by 19-2.5LF and then 19-2.5. In addition, 19-4LF was able to significantly reduce the parasite burden in the skin lesions of infected mice, as measured by quantifying L. major Lm18S ribosomal gene mRNA levels using qPCR. Moreover, when combined, the peptides exhibited synergistic effects on L. major promastigotes and significantly reduced the number of amastigotes in infected macrophages. Conclusions: These studies support the approach of repurposing these AMPs as antileishmanial drugs and identify 19-4LF as a lead candidate for further studies. While historical barriers to peptide therapeutics included high production costs, recent advancements in biological fermentation and synthesis strategies have significantly improved their economic viability. Furthermore, the use of nanotechnology delivery systems can reduce the required dosage, further making peptide therapy a sustainable option for neglected diseases, including leishmaniasis. Full article

Background/Objectives: Fosfomycin is an old antimicrobial agent historically used in its oral formulation for uncomplicated urinary tract infections. In the current context of rising antimicrobial resistance and limited antimicrobial options, fosfomycin has attracted renewed interest. Methods: A comprehensive review on the IV fosfomycin use focusing on critically ill patients and/or severe infections due to difficult-to-treat (DTR) Gram-negative bacilli (GNB). Results: Fosfomycin’s IV formulation is now being used more widely, particularly in critically ill patients with multidrug-resistant (MDR) or DTR-GNB infections. It offers several attractive features: a unique mechanism of action that minimizes cross-resistance; a broad spectrum of activity, covering both Gram-negative and Gram-positive pathogens; and consistent synergy with multiple pivotal antimicrobials. Its pharmacokinetic/pharmacodynamic (PK/PD) profile is favorable, with extensive tissue penetration, including the central nervous system. The ratio of area under the concentration–time curve to the minimum inhibitory concentration of the pathogen (AUC/MIC) is considered the optimal PK/PD target for fosfomycin. The adverse events are mainly non-serious (most frequently, hypernatremia and hypokalemia), although safety data for higher dosing regimens remain limited. Growing clinical evidence supports IV fosfomycin as an effective and well-tolerated component of combination therapy for severe infections in critically ill patients, including those infections caused by extended-spectrum beta-lactamases-, carbapenemase-producing Enterobacterales, and DTR non-fermentative GNB. Nevertheless, as with many rediscovered antimicrobials, its expanded role requires confirmation through rigorously designed clinical trials to better define its efficacy, optimal use, and safety profile in the treatment of severe DTR-GNB infections. Full article

Yersinia pestis and Francisella tularensis are Tier-1 pathogens with high interest for biodefense and public health. Evaluating the antibacterial activity of repurposed drugs against these high-priority pathogens is a key element in the ongoing effort to develop diversified antimicrobial strategies. Drug repurposing offers a cost-effective and time-efficient approach to address antibiotic resistance by identifying new applications for existing therapeutics. In this study, we demonstrate in vitro antibacterial effect of the antifungal agent ciclopirox and offer this drug as a potential antibacterial treatment. Ciclopirox in vitro activity was previously reported against various Gram-negative bacteria, including resistant strains, primarily through iron chelation that disrupts key metabolic pathways and virulence mechanisms. Additionally, it exhibits antibiofilm activity and can potentiate the efficacy of certain antibiotics. Our findings reveal that ciclopirox effectively inhibits the in vitro growth of fully virulent strains of Y. pestis and F. tularensis, as well as avirulent isolates, including avirulent mutants that their wild-type susceptibility was reduced through selection to MIC levels defining them as “nonsusceptible” to ciprofloxacin (Y. pestis Kim53Δ70Δ10 and F. tularensis LVS) and doxycycline (LVS), or resistant to doxycycline (Kim53Δ70Δ10) according to CLSI interpretive criteria. Additionally, prolonged exposure of Y. pestis and F. tularensis to sub-MIC and MIC concentrations of ciclopirox did not lead to an increase in observed MIC during the study period. These results highlight ciclopirox as a potential candidate for treatment alternative, combined with other antibiotic substances or repurposed drugs against these bacterial threats. Full article

The rapid global spread of antimicrobial resistance (AMR) has significantly reduced the effectiveness of many modern antibiotics, creating an urgent need for alternative therapeutic strategies. One promising approach is the revival and repurposing of older antimicrobial agents whose clinical potential was previously limited by toxicity concerns, pharmacokinetic challenges, or the availability of newer drugs. Recent advances in drug delivery, dosing optimization, and antimicrobial stewardship have renewed interest in these compounds as viable options for the treatment of multidrug-resistant infections. The aim of this review is to provide a comparative, clinically oriented analysis of selected “old” antibiotics, fosfomycin, colistin, streptomycin, and vancomycin, with emphasis on their current therapeutic roles, pharmacokinetic/pharmacodynamic (PK/PD) targets, toxicity mitigation strategies, resistance mechanisms, and evidence supporting combination therapies and alternative routes of administration. This narrative review was conducted using a structured PubMed search and manual reference screening, focusing on clinical, PK/PD, and translational studies relevant to the contemporary use of legacy antibiotics. The review summarises current evidence on the re-emerging clinical applications of these agents, each discussed in the context of historical use, mechanism of action, resistance patterns, and newly identified indications. Attention is given to novel formulations, combination strategies, and alternative routes of administration that enhance efficacy while limiting toxicity, including applications in biofilm-associated infections. Overall, strategic repurposing of older antibiotics represents a valuable complementary approach in the fight against AMR and may extend the therapeutic lifespan of existing agents in an era of limited antibiotic innovation. Full article

Disulfiram (DSF) is a well-established inhibitor of aldehyde dehydrogenases (ALDHs) and an FDA-approved drug for chronic alcoholism. DSF has gained attention as a versatile scaffold for drug repurposing. Its metabolite, diethyldithiocarbamate (DDTC), mediates multiple biological effects via metal chelation and covalent modification of key cysteine residues. Beyond its established anticancer properties, DSF modulates cancer stem cells, reactive oxygen species, proteasome function, and drug-resistance pathways. It also shows promise in metabolic disorders, including type 2 diabetes and obesity, by targeting enzymes such as fructose-1,6-bisphosphatase and α-glucosidase, and influences energy expenditure and autophagy. DSF exhibits antimicrobial and antiparasitic activity, enhances antibiotic efficacy against multidrug-resistant bacteria, and demonstrates antischistosomal and anti-Trichomonas effects, while also providing radioprotective benefits. The clinical translation of DSF is limited by poor solubility, rapid metabolism, and off-target effects; consequently, the development of DSF analogs has become a major focus. Structural optimization has yielded derivatives with improved selectivity, stability, solubility, and target specificity, enabling precise modulation of key enzymes while reducing adverse effects. A key structure-based strategy involves introducing bulkier substituents to exploit differences in ALDH active-site architecture and achieve target selectivity. This concept is exemplified by compounds (1) and (2), in which bulky substituents confer selective inhibition of ALDH1A1 while sparing ALDH2. This review provides a comprehensive overview of DSF analogs, their molecular mechanisms, and therapeutic potential, highlighting their promise as multifunctional agents for cancer, metabolic disorders, infectious diseases, and radioprotection. Full article

Every year, crustacean shell waste amounts to nearly 8 million tons worldwide, representing both an environmental challenge and a valuable resource. Crustacean shells can be repurposed as raw material for products in various industries, including agriculture, construction, and biomedicine. They are a valuable resource for creating functional materials due to their high content of chitin, protein, and calcium carbonate. These compounds can be extracted and processed to create various products, such as the biopolymer chitosan, antioxidants like astaxanthin, and adsorbents for water treatment, aligning with a circular economy approach by converting waste into valuable by-products. Chitosan films from crustacean waste are promising active packaging materials developed over the last decade, featuring enhanced antimicrobial and antioxidant properties. Extensive research confirms that crustacean shell waste is an excellent, low-cost adsorbent for removing heavy metals from water. This review analyzes current trends and opportunities for crustacean shell waste utilization in packaging materials and wastewater treatment. Key applications include replacing conventional plastic in biodegradable packaging and improving water treatment, which enhances resource efficiency and minimizes environmental pollution. Full article

Bovine mastitis remains a major challenge in dairy production despite extensive antimicrobial use, with therapeutic failure increasingly attributed to factors beyond classical antimicrobial resistance (AMR). Growing evidence indicates that treatment inefficacy arises from the combined effects of pharmacokinetic/pharmacodynamic (PK/PD) constraints, biofilm-mediated tolerance, intracellular persistence, and the adaptive capacity of mastitis pathogens. Intramammary therapy is particularly limited by poor tissue penetration, episodic drug elimination via milk flow, and inactivation by milk components, frequently resulting in subtherapeutic exposure at the site of infection. These limitations are amplified in chronic and subclinical mastitis, where biofilms and intracellular reservoirs reduce antimicrobial susceptibility and promote relapse and resistance selection. This narrative review integrates current knowledge on pharmacokinetic and pharmacodynamic (PK/PD) barriers, microbial survival strategies, and antimicrobial resistance (AMR) mechanisms that underlie treatment failure in bovine mastitis. It critically evaluates conventional antimicrobial therapies alongside emerging approaches, including antimicrobial peptides, bacteriophages and endolysins, nanoparticle-based delivery systems, immunomodulators, CRISPR-guided antimicrobials, and drug repurposing strategies. Overall, available evidence highlights the potential of these approaches to enhance therapeutic durability, particularly in settings where biofilm formation, intracellular persistence, and resistance limit conventional treatment efficacy. By mapping research coverage across mastitis phenotypes and therapeutic outcomes, this review identifies key gaps in long-term efficacy and resistance mitigation and underscores the need for PK/PD-guided, biofilm-aware, and resistance-conscious strategies to support durable next-generation mastitis management. Full article

Background: Heteroaromatic iodine-containing compounds have been previously recognized for their broad-spectrum antimicrobial activity. This study aims to systematically investigate their potential repurposing as anticancer agents, with a particular focus on understanding the structural determinants that influence their cytotoxicity and selectivity toward malignant cells. Methods: A series of heteroaromatic iodine-containing derivatives were synthesized and evaluated for anticancer activity. Their cytotoxic effects were measured and compared between cancerous and normal cell lines to determine selectivity. Structural features, including heteroaromatic moieties and substituents, were analyzed to identify correlations with biological activity. Results: Among the tested compounds, derivatives 3e, 3g, and 3l demonstrated significant cytotoxic effects while exhibiting favorable selectivity indices. These findings indicate that these compounds preferentially target malignant cells over normal cells, thereby mitigating the issue of systemic toxicity often associated with traditional chemotherapeutics. The enhanced anticancer activity appears to be influenced by specific structural elements within the heteroaromatic framework. Conclusions: The study highlights the potential of heteroaromatic iodine-containing compounds as promising anticancer candidates. Rational structural modifications within these heterocyclic systems can effectively modulate bioactivity and improve therapeutic selectivity. These results support further development of this compound class for anticancer applications. Full article

Non-tuberculous mycobacteria (NTM) comprise more than 190 species capable of causing severe pulmonary, lymphatic, cutaneous, and disseminated infections, particularly in immunocompromised populations. Over the past two decades, the global incidence of NTM infections has risen steadily, underscoring an urgent unmet medical need. Treatment remains highly challenging due to intrinsic antimicrobial resistance and the requirement for prolonged multidrug regimens that are often poorly tolerated and associated with unsatisfactory outcomes. At the same time, the development of novel therapies has lagged behind other disease areas, hindered by the high costs of antimicrobial drug discovery and the relatively low commercial return compared with treatments for chronic conditions. Over the past decade, discovery and development have diversified across novel small molecules, next-generation analogues of existing classes, and adjunctive or host-directed strategies. While most candidates remain preclinical, several agents have advanced clinically in other infections, including gepotidacin (topoisomerase inhibitor; FDA-approved 2025 for urinary tract infection (UTI)), sulbactam–durlobactam (DBO β-lactamase inhibitor; FDA-approved 2023 for Acinetobacter baumannii complex), and contezolid, supporting repurposing opportunities for NTM. Conversely, SPR720 (gyrase B prodrug) was suspended after not meeting its Phase 2 endpoint in 2024, underscoring translational risk. Overall, the NTM pipeline is expanding, with near-term progress most likely from repurposed agents and optimised combinations, alongside earlier-stage candidates that target biofilms or resistance mechanisms. This review aims to provide a critical and up-to-date overview of emerging antimicrobial strategies against NTM, highlighting recent advances, translational challenges, and opportunities to accelerate the development of effective therapeutics. Full article

Background/Objective: American tegumentary leishmaniasis is a neglected tropical disease with limited therapeutic options characterized by high toxicity and poor tolerability. Drug repurpose offers a pragmatic strategy to accelerate the development of safer treatments. This study evaluated the antileishmanial activity of three clinically approved acetylcholinesterase (AChE) inhibitors—donepezil hydrochloride (DH), rivastigmine tartrate (RT), and galantamine hydrobromide (GH), tested individually and in combination with amphotericin B (AmpB) against Leishmania species relevant to tegumentary leishmaniasis. Methods: Antileishmanial activity was assessed against Leishmania (Leishmania) amazonensis promastigotes and intracellular amastigotes and Leishmania (Viannia) braziliensis promastigotes and axenic amastigotes. Cytotoxicity was evaluated in mammalian cell lines. The synergy with AmpB was analyzed at different proportions. Mechanistic studies included morphological analysis using light and scanning electron microscopy, flow cytometry, AChE activity assays, choline supplementation experiments, and membrane fluidity measurements. Results: All three AChE inhibitors demonstrated antileishmanial activity with selectivity indices > 1. DH emerged as the most promising candidate (IC₅₀ = 16.82 μM against promastigotes; SI = 10.25), with superior potency compared to other repurposed drugs. Strong synergistic interactions with AmpB were observed for all inhibitors (χΣFIC ≤ 0.17), with DH-AmpB displaying the most robust synergy (χΣFIC = 0.09), reducing the IC ₅₀ of AmpB by nearly 90-fold. DH induced distinct morphological alterations and acted through non-cholinergic mechanisms. The DH-AmpB combination retained maximal efficacy against L. (V.) braziliensis, with enhanced activity against clinically relevant amastigotes. Conclusions: Repurposed AChE inhibitors, particularly donepezil hydrochloride, are highly promising therapeutic candidates for tegumentary leishmaniasis. The robust synergistic effect with amphotericin B, together with their favorable safety profiles and non-antimicrobial mechanisms, positions these drugs as viable partners in dose-sparing combination regimens that could improve treatment adherence and reduce toxicity in endemic areas. Full article