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Multi-drug resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a global health threat. The severity of the problem lies in its impact on mortality, therapeutic limitations, the threat to public health, and the costs associated with managing infections caused by these resistant strains. Effectively addressing this challenge requires innovative approaches to research, the development of new antimicrobials, and more responsible antibiotic use practices globally. Antimicrobial peptides (AMPs) are a part of the innate immune system of all higher organisms. They are short, cationic and amphipathic molecules with broad-spectrum activity. AMPs interact with the negatively charged bacterial membrane. In recent years, AMPs have attracted considerable interest as potential antibiotics. However, AMPs have low bioavailability and short half-lives, which may be circumvented by chemical modification. This review presents recent in vitro and in silico strategies for the modification of AMPs to improve their stability and application in preclinical experiments.
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Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose a significant threat to global health. The resilience of TB is amplified by a myriad of physical, biological, and biopharmaceutical barriers that challenge conventional therapeutic approaches. This review navigates the intricate landscape of TB treatment, from the stealth of latent infections and the strength of granuloma formations to the daunting specters of drug resistance and altered gene expression. Amidst these challenges, traditional therapies often fail, contending with inconsistent bioavailability, prolonged treatment regimens, and socioeconomic burdens. Nanoscale Drug Delivery Systems (NDDSs) emerge as a promising beacon, ready to overcome these barriers, offering better drug targeting and improved patient adherence. Through a critical approach, we evaluate a spectrum of nanosystems and their efficacy against MTB both in vitro and in vivo. This review advocates for the intensification of research in NDDSs, heralding their potential to reshape the contours of global TB treatment strategies.
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INTRODUCTION: Tuberculosis remains a significant concern in global public health due to its intricate biology and propensity for developing antibiotic resistance. Discovering new drugs is a protracted and expensive endeavor, often spanning over a decade and incurring costs in the billions. However, computer-aided drug design (CADD) has surfaced as a nimbler and more cost-effective alternative. CADD tools enable us to decipher the interactions between therapeutic targets and novel drugs, making them invaluable in the quest for new tuberculosis treatments. AREAS COVERED: In this review, the authors explore recent advancements in tuberculosis drug discovery enabled by in silico tools. The main objectives of this review article are to highlight emerging drug candidates identified through in silico methods and to provide an update on the therapeutic targets associated with Mycobacterium tuberculosis. EXPERT OPINION: These in silico methods have not only streamlined the drug discovery process but also opened up new horizons for finding novel drug candidates and repositioning existing ones. The continued advancements in these fields hold great promise for more efficient, ethical, and successful drug development in the future.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Diseño de Fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Descubrimiento de Drogas , Desarrollo de Medicamentos , Diseño Asistido por ComputadoraRESUMEN
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, most known as ulcerative colitis (UC) and Crohn's disease (CD), that affects the gastrointestinal tract (GIT), causing considerable symptoms to millions of people around the world. Conventional therapeutic strategies have limitations and side effects, prompting the exploration of innovative approaches. Probiotics, known for their potential to restore gut homeostasis, have emerged as promising candidates for IBD management. Probiotics have been shown to minimize disease symptoms, particularly in patients affected by UC, opening important opportunities to better treat this disease. However, they exhibit limitations in terms of stability and targeted delivery. As several studies demonstrate, the encapsulation of the probiotics, as well as the synthetic drug, into micro- and nanoparticles of organic materials offers great potential to solve this problem. They resist the harsh conditions of the upper GIT portions and, thus, protect the probiotic and drug inside, allowing for the delivery of adequate amounts directly into the colon. An overview of UC and CD, the benefits of the use of probiotics, and the potential of micro- and nanoencapsulation technologies to improve IBD treatment are presented. This review sheds light on the remarkable potential of nano- and microparticles loaded with probiotics as a novel and efficient strategy for managing IBD. Nonetheless, further investigations and clinical trials are warranted to validate their long-term safety and efficacy, paving the way for a new era in IBD therapeutics.
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The search for new antimicrobial agents is a continuous struggle, mainly because more and more cases of resistant strains are being reported. Mycobacterium tuberculosis (MTB) is the main microorganism responsible for millions of deaths worldwide. The development of new antimicrobial agents is generally aimed at finding strong interactions with one or more bacterial receptors. It has been proven that bacteriophages have the ability to adhere to specific and selective regions. However, their transport and administration must be carefully evaluated as an excess could prevent a positive response and the bacteriophages may be eliminated during their journey. With this in mind, the mycobacteriophage D29 was encapsulated in nanoliposomes, which made it possible to determine its antimicrobial activity during transport and its stability in the treatment of active and latent Mycobacterium tuberculosis. The antimicrobial activity, the cytotoxicity in macrophages and fibroblasts, as well as their infection and time-kill were evaluated. Phage nanoencapsulation showed efficient cell internalization to induce MTB clearance with values greater than 90%. Therefore, it was shown that nanotechnology is capable of assisting in the activity of degradation-sensitive compounds to achieve better therapy and evade the immune response against phages during treatment.
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Latent tuberculosis infection (LTBI) represents a subclinical, asymptomatic mycobacterial state affecting approximately 25% of the global population. The substantial prevalence of LTBI, combined with the risk of progressing to active tuberculosis, underscores its central role in the increasing incidence of tuberculosis (TB). Accurate identification and timely treatment are vital to contain and reduce the spread of the disease, forming a critical component of the global strategy known as "End TB." This review aims to examine and highlight the most recent scientific evidence related to new diagnostic approaches and emerging therapeutic treatments for LTBI. While prevalent diagnostic methods include the tuberculin skin test (TST) and interferon gamma release assay (IGRA), WHO's approval of two specific IGRAs for Mycobacterium tuberculosis (MTB) marked a significant advancement. However, the need for a specific test with global application viability has propelled research into diagnostic tests based on molecular diagnostics, pulmonary immunity, epigenetics, metabolomics, and a current focus on next-generation MTB antigen-based skin test (TBST). It is within these emerging methods that the potential for accurate distinction between LTBI and active TB has been demonstrated. Therapeutically, in addition to traditional first-line therapies, anti-LTBI drugs, anti-resistant TB drugs, and innovative candidates in preclinical and clinical stages are being explored. Although the advancements are promising, it is crucial to recognize that further research and clinical evidence are needed to solidify the effectiveness and safety of these new approaches, in addition to ensuring access to new drugs and diagnostic methods across all health centers. The fight against TB is evolving with the development of more precise diagnostic tools that differentiate the various stages of the infection and with more effective and targeted treatments. Once consolidated, current advancements have the potential to transform the prevention and treatment landscape of TB, reinforcing the global mission to eradicate this disease.
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This study aimed to evaluate Attalea funifera seed oil with or without resveratrol entrapped in organogel nanoparticles in vitro against A375 human melanoma tumor cells. Organogel nanoparticles with seed oil (SON) or with resveratrol entrapped in the seed oil (RSON) formed functional organogel nanoparticles that showed a particle size <100 nm, polydispersity index <0.3, negative zeta potential, and maintenance of electrical conductivity. The resveratrol entrapment efficiency in RSON was 99 ± 1%. The seed oil and SON showed no cytotoxicity against human non-tumor cells or tumor cells. Resveratrol at 50 µg/mL was cytotoxic for non-tumor cells, and was cytotoxic for tumor cells at 25 µg/mL. Resveratrol entrapped in RSON showed a decrease in cytotoxicity against non-tumor cells and cytotoxic against tumor cells at 50 µg/mL. Thus, SON is a potential new platform for the delivery of resveratrol with selective cytotoxic activity in the treatment of melanoma.
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Antineoplásicos , Arecaceae , Melanoma , Nanogeles , Sistema de Administración de Fármacos con Nanopartículas , Aceite de Palma , Resveratrol , Resveratrol/administración & dosificación , Melanoma/terapia , Humanos , Línea Celular Tumoral , Nanogeles/administración & dosificación , Nanogeles/química , Arecaceae/química , Aceite de Palma/química , Semillas/química , Tamaño de la Partícula , Antineoplásicos/administración & dosificación , Antineoplásicos/químicaRESUMEN
Tuberculosis and lung cancer are, in many cases, correlated diseases that can be confused because they have similar symptoms. Many meta-analyses have proven that there is a greater chance of developing lung cancer in patients who have active pulmonary tuberculosis. It is, therefore, important to monitor the patient for a long time after recovery and search for combined therapies that can treat both diseases, as well as face the great problem of drug resistance. Peptides are molecules derived from the breakdown of proteins, and the membranolytic class is already being studied. It has been proposed that these molecules destabilize cellular homeostasis, performing a dual antimicrobial and anticancer function and offering several possibilities of adaptation for adequate delivery and action. In this review, we focus on two important reason for the use of multifunctional peptides or peptides, namely the double activity and no harmful effects on humans. We review some of the main antimicrobial and anti-inflammatory bioactive peptides and highlight four that have anti-tuberculosis and anti-cancer activity, which may contribute to obtaining drugs with this dual functionality.
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This work describes the preparation, characterization and antimicrobial activity of four palladium(II) complexes, namely, [Pd(meg)(1,10-phen)] 1, [Pd(meg)(PPh3)2] 2, [Pd(og)(1,10-phen)] 3 and [Pd(og)(PPh3)2] 4, where meg = methyl gallate, og = octyl gallate, 1,10-phen = 1,10-phenanthroline and PPh3 = triphenylphosphine. As to the chemical structures, spectral and physicochemical studies of 1-4 indicated that methyl or octyl gallate coordinates a palladium(II) ion through two oxygen atoms upon deprotonation. A chelating bidentate phenanthroline or two triphenylphosphine molecules complete the coordination sphere of palladium(II) ion, depending on the complex. The metal complexes were tested against the Mycobacterium tuberculosis H37Rv strain and 2 exhibited high activity (MIC = 3.28 µg/mL). As to the tests with Campylobacter jejuni, complex 1 showed a significant effect in reducing bacterial population (greater than 7 log CFU) in planktonic forms, as well as in the biomass intensity (IBF: 0.87) when compared to peracetic acid (IBF: 1.11) at a concentration of 400 µg/mL. The effect provided by these complexes has specificity according to the target microorganism and represent a promising alternative for the control of microorganisms of public health importance.
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Campylobacter jejuni , Complejos de Coordinación , Mycobacterium tuberculosis , Paladio/farmacología , Paladio/química , Cristalografía por Rayos X , Complejos de Coordinación/farmacología , Complejos de Coordinación/químicaRESUMEN
The incorrect use of conventional drugs for both prevention and control of intestinal infections has contributed to a significant spread of bacterial resistance. In this way, studies that promote their replacement are a priority. In the last decade, the use of antimicrobial peptides (AMP), especially Ctx(Ile21)-Ha AMP, has gained strength, demonstrating efficient antimicrobial activity (AA) against pathogens, including multidrug-resistant bacteria. However, gastrointestinal degradation does not allow its direct oral application. In this research, double-coating systems using alginate microparticles loaded with Ctx(Ile21)-Ha peptide were designed, and in vitro release assays simulating the gastrointestinal tract were evaluated. Also, the AA against Salmonella spp. and Escherichia coli was examined. The results showed the physicochemical stability of Ctx(Ile21)-Ha peptide in the system and its potent antimicrobial activity. In addition, the combination of HPMCAS and chitosan as a gastric protection system can be promising for peptide carriers or other low pH-sensitive molecules, adequately released in the intestine. In conclusion, the coated systems employed in this study can improve the formulation of new foods or biopharmaceutical products for specific application against intestinal pathogens in animal production or, possibly, in the near future, in human health.
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Antiinfecciosos , Quitosano , Animales , Humanos , Quitosano/química , Alginatos/química , Péptidos Antimicrobianos , Antiinfecciosos/farmacologíaRESUMEN
As a biologic reservoir of Mycobacterium tuberculosis (M. tb), one-quarter of the world population is infected with the well-known latent tuberculosis (LTBI). About 5-10% of LTBI patients will progress to active disease in the first years after primary infection and, despite using the recommended treatment, 20% can still reactivate the infection. A new LTBI treatment could minimize adverse effects and antibiotic resistance that can occur when the same drug is used to treat the latent and active disease. New hydrazones were evaluated, and they showed great inhibitory activity against intramacrophagic and non-replicating M. tb, commonly found at this stage of infection, in addition to bactericidal and narrow-spectrum activity. When tested against eukaryotic cells, the hydrazones showed great safety at different exposure times. In vitro, these compounds performed better than isoniazid and could be considered new candidates for LTBI treatment, which may promote greater engagement in its prescription and adherence.
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For the first time, we herein report on the syntheses of two new Ru(II)/bipyridine/phenanthroline complexes containing lapachol as ligand: complex (1), [Ru (bipy)2(Lap)]PF6 and complex (2), [Ru(Lap)(phen)2]PF6, where bipy = 2,2'-bipyridine and ph en = 1,10-phenanthroline; Lap = lapachol (2-hydroxy-3-(3-methylbut-2-en-1- yl)naphthalene-1,4-dione). The complexes were synthesized and characterized by elemental analyses, molar conductivity, mass spectrometry, ultraviolet-visible and infrared spectroscopies, nuclear magnetic resonance (1H, 13C), and single crystal X-ray diffraction, for complex (2). In addition, in vitro cytotoxicity was tested against six cancer cells: A549 (lung carcinoma); DU-145 (human prostate carcinoma); HepG2 (human hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma); MDA-MB-231 (human breast adenocarcinoma); Caco-2 (human colorectal adenocarcinoma), and against two non-cancer cells, FGH (human gingival normal fibroblasts) and PNT-2 (prostate epithelial cells). Complex (1) was slightly more toxic and selective than complex (2) for all cell lines, except against the A549 cells, where (2) was more potent than complex (1). The complexes induced an increase in the reactive oxygen species, and the co-treatment with N-acetyl-L-cysteine remarkably suppressed the ROS generation and prevented the reduction of cell viability, suggesting that the cytotoxicity of the complexes is related to the ROS-mediated pathway. Further studies indicated that the complexes may bind to DNA via minor groove interaction. Our studies also revealed that free Lap induces gene mutations in Salmonella Typhimurium, nevertheless, the complexes demonstrated the absence of genotoxicity by the Ames test. The present study provides a relevant contribution to understanding the anti-cancer potential and genetic toxicological events of new ruthenium complexes containing the lapachol molecule as a ligand.
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Adenocarcinoma , Antineoplásicos , Carcinoma , Complejos de Coordinación , Rutenio , Masculino , Humanos , Fenantrolinas , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Especies Reactivas de Oxígeno/metabolismo , Ligandos , Células CACO-2 , Rutenio/química , Antineoplásicos/química , Línea Celular TumoralRESUMEN
Since 1966, rifampicin (RIF) has been considered one of the most potent drugs in the treatment of tuberculosis (TB), which is caused by infection with M. tuberculosis (Mtb). New nanostructured formulations for RIF delivery and alternative routes of administration have been studied as potential forms of treatment. This study evaluates a liquid crystal system for RIF delivery, using alternative drug delivery routes. The systems developed are composed of surfactant, oleylamine, and soy phosphatidylcholine. With the aid of polarized light microscopy, it was possible to determine that the developed systems had a hexagonal mesophase. All systems developed showed non-Newtonian pseudoplasticity and a high degree of thixotropy. Liquid crystal systems with RIF showed an increase in elastic potential, indicating greater mu-coadhesiveness. The evaluation of mucoadhesive forces revealed an increase in the mucoadhesive potential in the presence of mucus, indicating the presence of satisfactory mucoadhesive forces. The 9DR and 10DR liquid crystal systems, when submitted to Differential Scanning Calorimetry analysis, remained structured even at temperatures above 100 °C, showing excellent stability. The developed liquid crystal systems showed a tolerable degree of cytotoxicity and bactericidal potential, for example, the 9DR system demonstrated a reduction in bacterial load after the third day and reached zero CFU on the seventh day of the test. The developed systems were also evaluated in the preclinical model of Mtb-infected mice, using the nasal, sublingual, and cutaneous route for the delivery of RIF associated with a nanostructured liquid crystal system as a possible tool in the treatment of TB.
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Biotechnology and pharmacy have shown efficient results when combined to generate innovative technological products [...].
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The importance of obtaining new compounds with improved antimicrobial activity is a current trend and challenge. Some polymers such as chitosan have shown promising bactericidal properties when they are structurally modified, which is due to the binding versatility provided by their free amines. Likewise, antimicrobial peptides (AMPs) have received attention in recent years because of their bactericidal activity that is similar to or even better than that of conventional drugs, and they exhibit a low induction rate of antimicrobial resistance. Herein, the modified AMP Ctx(Ile21)-Ha-Ahx-Cys was conjugated to chitosan using N-acetylcysteine as an intermediate by the carbodiimide method. Films were prepared using protonated chitosan in 1% acetic acid and Ctx(Ile21)-Ha-Ahx-Cys AMP dissolved in N-acetylcysteine-chitosan; 1.6 mmol of ethylcarbodiimide hydrochloride, 1.2 mmol of N-hydroxysulfosucchimide, and 0.1 mol L -1of N-morpholino)ethanesulfonic acid buffer at pH 6.5 by continuous stirring at 100 × g for 10 min at 37 °C. Physicochemical properties were evaluated by Fourier-transform infrared spectroscopy, differential scanning calorimetry/thermogravimetric analysis, and X-ray diffraction to determine the mechanical properties, solubility, morphology, and thickness. Furthermore, the antimicrobial activities of chitosan-based conjugated films were evaluated againstStaphylococcus aureus,Pseudomonas aeruginosa,SalmonellaTyphimurium, andEscherichia coli. The results showed that the conjugation of a potent AMP could further increase its antibacterial activity and maintain its stable physicochemical properties. Therefore, the developed peptide-chitosan conjugate could be applied as an additive in surgical procedures to prevent and combat bacterial infection.
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Nanoparticles of metal-organic frameworks (MOF NPs) are crystalline hybrid micro- or mesoporous nanomaterials that show great promise in biomedicine due to their significant drug loading ability and controlled release. Herein, we develop porous capsules from aggregate of nanoparticles of the iron carboxylate MIL-100(Fe) through a low-temperature spray-drying route. This enables the concomitant one-pot encapsulation of high loading of an antitumor drug, methotrexate, within the pores of the MOF NPs, and the collagenase enzyme (COL), inside the inter-particular mesoporous cavities, upon the formation of the capsule, enhancing tumor treatment. This association provides better control of the release of the active moieties, MTX and collagenase, in simulated body fluid conditions in comparison with the bare MOF NPs. In addition, the loaded MIL-100 capsules present, against the A-375 cancer cell line, selective toxicity nine times higher than for the normal HaCaT cells, suggesting that MTX@COL@MIL-100 capsules may have potential application in the selective treatment of cancer cells. We highlight that an appropriate level of collagenase activity remained after encapsulation using the spray dryer equipment. Therefore, this work describes a novel application of MOF-based capsules as a dual drug delivery system for cancer treatment.
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Estructuras Metalorgánicas , Nanopartículas , Neoplasias , Humanos , Cápsulas , Sistemas de Liberación de Medicamentos , Estructuras Metalorgánicas/química , Nanopartículas/química , Neoplasias/tratamiento farmacológicoRESUMEN
Vitamins are widely found in nature, for example, in plants and fruits. Ascorbic acid and nicotinamide are examples of these compounds that have potent antioxidant properties, besides stimulating collagen production and depigmenting properties that protect the skin from premature aging. To overcome the skin barrier and reduce the instability of antioxidant compounds, alternative systems have been developed to facilitate the delivery of antioxidants, making them efficiently available to the tissue for an extended time without causing damage or toxicity. The objective of this study was to obtain chitosan biodegradable microparticles containing ascorbic acid and nicotinamide for topical delivery. The microparticles were obtained by spray drying and characterized chemically by means of scanning electron microscopy, infrared spectroscopy, X-ray diffraction, and differential exploratory calorimetry. The drugs were successfully encapsulated and the microparticles showed positive zeta potential. In vitro release assays showed a sustained release profile. The evaluation of ex vivo skin permeation and retention demonstrated low permeation and adequate retention of the compounds in the epidermis/dermis, suggesting the efficient delivery from the obtained microparticles. Antibacterial assays have shown that microparticles can inhibit the growth of microorganisms in a time- and dose-dependent manner, corroborating their use in cosmetic products for application on the skin.
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Some diseases of uncontrolled proliferation such as cancer, as well as infectious diseases, are the main cause of death in the world, and their causative agents have rapidly developed resistance to the various existing treatments, making them even more dangerous. Thereby, the discovery of new therapeutic agents is a challenge promoted by the World Health Organization (WHO). Biomacromolecules, isolated or synthesized from a natural template, have therapeutic properties which have not yet been fully studied, and represent an unexplored potential in the search for new drugs. These substances, starting from conglomerates of proteins and other substances such as animal venoms, or from minor substances such as bioactive peptides, help fight diseases or counteract harmful effects. The high effectiveness of these biomacromolecules makes them promising substances for obtaining new drugs; however, their low bioavailability or stability in biological systems is a challenge to be overcome in the coming years with the help of nanotechnology. The objective of this review article is to describe the relationship between the structure and function of biomacromolecules of animal origin that have applications already described using nanotechnology and targeted delivery.
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An exploration of the chemical space around a 2,5-dimethylpyrrole scaffold of antitubercular hit compound 1 has led to the identification of new derivatives active against Mycobacterium tuberculosis and multidrug-resistant clinical isolates. Analogues incorporating a cyclohexanemethyl group on the methyleneamine side chain at C3 of the pyrrole core, including 5n and 5q, exhibited potent inhibitory effects against the M. tuberculosis strains, substantiating the essentiality of the moiety to their antimycobacterial activity. In addition, selected derivatives showed promising cytotoxicity profiles against human pulmonary fibroblasts and/or murine macrophages, proved to be effective in inhibiting the growth of intracellular mycobacteria, and elicited either bactericidal effects, or bacteriostatic activity comparable to 1. Computational studies revealed that the new compounds bind to the putative target, MmpL3, in a manner similar to that of known inhibitors BM212 and SQ109.
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Antituberculosos , Mycobacterium tuberculosis , Animales , Antituberculosos/química , Antituberculosos/farmacología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Pirroles/química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis) in poultry is most often transmitted by the fecal-oral route, which can be attributed to high population density. Upon encountering the innate immune response in a host, the pathogen triggers a stress response and virulence factors to help it survive in the host. The aim of this study was to evaluate the effect of hypromellose acetate/succinate (HPMCAS)-coated alginate microparticles containing the Ctx(Ile21)-Ha antimicrobial peptide (AMP) on both intestinal colonization and systemic infection of laying hens challenged with S. Enteritidis. The applied AMP microsystem reduced the bacterial load of S. Enteritidis in the liver, with a statistical significance between groups A (control, no Ctx(Ile21)-Ha peptide) and B (2.5 mg of Ctx(Ile21)-Ha/kg) at 2 days postinfection (dpi), potentially indicating the effectiveness of Ctx(Ile21)-Ha in the first stage of infection by S. Enteritidis. In addition, the results showed a significant decrease in the S. Enteritidis counts in the spleen and cecal content at 5 dpi; remarkably, no S. Enteritidis counts were observed in livers at 5, 7, and 14 dpi, regardless of the Ctx(Ile21)-Ha dosage (p-value <0.0001). Using the Chi-square test, the effect of AMP microparticles on S. Enteritidis fecal excretion was also evaluated, and a significantly lower bacterial excretion was observed over 21 days in groups B and C, in comparison with the untreated control (p-value <0.05). In summary, the use of HPMCAS-Ctx(Ile21)-Ha peptide microcapsules in laying hens drastically reduced the systemic infection of S. Enteritidis, mainly in the liver, indicating a potential for application as a feed additive against this pathogen.