ESS - CQB - Ciências Químicas e das Biomoléculas
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Browsing ESS - CQB - Ciências Químicas e das Biomoléculas by Author "Aguiar, Luísa"
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- Boosting cosmeceutical peptides: coupling imidazolium-based ionic liquids to pentapeptide-4 originates new leads with antimicrobial and collagenesis-inducing activitiesPublication . Gomes, Ana; Bessa, Lucinda J.; Fernandes, Iva; Aguiar, Luísa; Ferraz, Ricardo; Monteiro, Cláudia; Martins, M. Cristina L.; Mateus, Nuno; Gameiro, Paula; Teixeira, Cátia; Gomes, PaulaFollowing our previous reports on dual-action antibacterial and collagenesis-inducing hybrid peptide constructs based on “pentapeptide-4” (PP4, with amino acid sequence KTTKS), whose N-palmitoyl derivative is the well-known cosmeceutical ingredient Matrixyl, herein we disclose novel ionic liquid/PP4 conjugates (IL-KTTKS). These conjugates present potent activity against either antibiotic-susceptible strains or multidrug resistant clinical isolates of both Gram-positive and Gram-negative bacterial species belonging to the so-called “ESKAPE” group of pathogens. Noteworthy, their antibacterial activity is preserved in simulated wound fluid, which anticipates an effective action in the setting of a real wound bed. Moreover, their collagenesis-inducing effects in vitro are comparable to or stronger than those of Matrixyl. Altogether, IL-KTTKS exert a triple antibacterial, antifungal, and collagenesis-inducing action in vitro. These findings provide solid grounds for us to advance IL-KTTKS conjugates as promising leads for future development of topical treatments for complicated skin and soft tissue infections (cSSTI). Further studies are envisaged to incorporate IL-conjugates into suitable nanoformulations, to reduce toxicity and/or improve resistance to proteolytic degradation.
- Cinnamic acid conjugates in the rescuing and repurposing of classical antimalarial drugsPublication . Silva, Ana Teresa; Bento, Clara M.; Pena, Ana C.; Figueiredo, Luísa M.; Prudêncio, Cristina; Aguiar, Luísa; Silva, Tânia; Ferraz, Ricardo; Gomes, Maria Salomé; Teixeira, Cátia; Gomes, PaulaCinnamic acids are compounds of natural origin that can be found in many different parts of a wide panoply of plants, where they play the most diverse biological roles, often in a conjugated form. For a long time, this has been driving Medicinal Chemists towards the investigation of the therapeutic potential of natural, semi-synthetic, or fully synthetic cinnamic acid conjugates. These efforts have been steadily disclosing promising drug leads, but a wide chemical space remains that deserves to be further explored. Amongst different reported approaches, the combination or conjugation of cinnamic acids with known drugs has been addressed in an attempt to produce either synergistic or multi-target action. In this connection, the present review will focus on efforts of the past decade regarding conjugation with cinnamic acids as a tool for the rescuing or the repurposing of classical antimalarial drugs, and also on future perspectives in this particular field of research.
- Drug-derived surface-active ionic liquids: a cost-effective way to expressively increase the blood-stage antimalarial activity of primaquinePublication . Silva, Ana Teresa; Oliveira, Isabel S.; Gomes, Joana; Aguiar, Luísa; Fontinha, Diana; Duarte, Denise; Nogueira, Fátima; Prudêncio, Miguel; Marques, Eduardo F.; Teixeira, Cátia; Ferraz, Ricardo; Gomes, PaulaInspired by previous disclosure of room-temperature ionic liquids derived from primaquine and cinnamic acids, which displayed slightly enhanced blood-stage activity compared to the parent drug, we have now combined this emblematic antimalarial with natural fatty acids. This affords surface-active ionic liquids whose liver-stage antiplasmodial activity is either retained or slightly enhanced, while revealing blood-stage antiplasmodial activity at least one order of magnitude higher than that of the parent compound. These findings open new perspectives towards the cost-effective recycling of classical drugs that are either shelved or in decline, and which is not limited to antimalarial agents.
- Improving the antimycobacterial drug Clofazimine through formation of organic salts by combination with fluoroquinolonesPublication . Bento, Clara M.; Silva, Ana Teresa; Mansano, Bruno; Aguiar, Luísa; Teixeira, Cátia; Gomes, Maria Salomé; Gomes, Paula; Silva, Tânia; Ferraz, RicardoThis work reports the synthesis, structural and thermal analysis, and in vitro evaluation of the antimicrobial activity of two new organic salts (OSs) derived from the antimycobacterial drug clofazimine and the fluoroquinolones ofloxacin or norfloxacin. Organic salts derived from active pharmaceutical ingredients (API-OSs), as those herein disclosed, hold promise as cost-effective formulations with improved features over their parent drugs, thus enabling the mitigation of some of their shortcomings. For instance, in the specific case of clofazimine, its poor solubility severely limits its bioavailability. As compared to clofazimine, the clofazimine-derived OSs now reported have improved solubility and thermostability, without any major deleterious effects on the drug’s bioactivity profile.
- Ionic liquids on the rescuing of conventional antimycobacterial drugsPublication . Bento, Clara M.; Silva, Tânia; Aguiar, Luísa; Teixeira, Cátia; Gomes, Paula; Ferraz, Ricardo; Gomes, Maria SaloméThe incidence of infections by nontuberculous mycobacteria (NTM) is increasing worldwide, mainly those caused by Mycobacterium avium complex (MAC) species. NTM are opportunistic pathogens that infect immunocompromised patients, namely those infected with HIV, with cancer or who were subject to a transplant. NTM are highly infectious and cause persistent infections due to their ability to easily form aerosols, to settle as biofilms and to resist to harsh environments, like chlorinated water. In the host, mycobacteria proliferate inside phagocytic cells, such as macrophages. There, they multiply inside small vacuoles and control the intracellular vesicular trafficking inhibiting the phagosome-lysosome fusion, which allowsthem to escape the lysosomal acidic environment and to have access to nutrients. NTM infections manifest primarily as pulmonary diseases, but can also affect other regions of the body, like the central nervous system, and cause lymphadenitis, which is the most common NTM-associated disease in immunocompetent children. The treatment basis of slow-growing NTM, in which MAC is included, is a macrolide. Clarithromycin or azithromycin are the usual options. A regimen of monotherapy with macrolides is, however, very dangerous as it will often lead to drug resistance and consequent treatment failure. Thus, a three-drug macrolide-based regimen with ethambutol and a rifamycin, which usually lasts from 6 to 12 months, is the recommended treatment. The addition of a fourth drug to the regimen, like aminoglycosides or a fluoroquinolone, can beimportant in more severe cases and is essential in cases of macrolide-resistant MAC. A very long multi-drug regimen like this, results in several issues to the patients, which decreases the probability of treatment success. It is thus urgent to finda new strategy to treat mycobacterial infections, including the repurposing of old drugs. Ionic liquids (ILs) are organic saltsmade by the combination of two molecules with opposite polarities. Their remarkable physical and chemical properties contributed for their extensive use as green-solvents, improving the performance and safety of chemical procedures, as well as vehicles in sensors and drug delivery systems. Recently, ILs have gained much attention in the area of drug development as antimicrobial agents, since they have shown improved solubility and bioavailability when compared to clinically approved drugs. The right combination of cations and anions can provide innovative compounds that help combat resistance issues. The aimof our work is to evaluate the capacity of ILs based on conventional antimycobacterial drugs to inhibit the viability and growthof M. avium in axenic culture and inside bone marrow-derived macrophages (BMM). We are assessing if the activity and toxicity of these compounds are improved by being in the IL form instead of being administered individually or in combination. Our results show that ILs derived from each of two fluoroquinolones, ofloxacin or norfloxacin, and the antimycobacterial drugclofazimine cause a more significant decrease in the extracellular and intracellular mycobacterial viability than the fluoroquinolones administered individually. Moreover, the ILs are less toxic to the host cells than clofazimine. Another pairofILs, which combine one classical antimalarial drug, chloroquine or primaquine, with the anti-tuberculosis drug aminosalicylic acid, also shows promising results: the ILs are more active against M. avium growing inside BMM than the three parental drugs by themselves. Therefore, our data encourage us to continue combining conventional anti-NTM antibiotics with molecules active against other pathogens in an IL form as a way to enhance their activity, improve pharmacological issues and combat resistances. In the future, we aim to test these ILs in more complex in vitro models of infection, such as biofilms and in vitrogranulomas, taking advantage of fluorescent and bioluminescent reporter strains of M. avium, in order to better predict theirclinical outcome and reduce the use of animals in preliminary drug testing.
- Peptide-ionic liquid conjugates towards the treatment of skin infectionsPublication . Gomes, Ana; Bessa, Lucinda; Fernandes, Iva; Teixeira, Cátia; Aguiar, Luísa; Ferraz, Ricardo; Monteiro, Cláudia; Martins, Cristina; Mateus, Nuno; Gameiro, Paula; Gomes, PaulaThe treatment of complicated skin infections, like diabetic foot ulcers and other chronic wounds, are often associated with persistent polymicrobial biofilms that delay and difficult the healing process. The most severe cases culminate in inpatient hospital admission, where infections can be exacerbated by hospital-acquired pathogens, in particular, if caused by the so-called ESKAPE pathogens, for which few efficient antibiotics are available. The current biomedical approaches to chronic wounds aim at providing both protection against multidrug-resistant (MDR) bacteria and a matrix scaffold, often collagen-based, to boost the reestablishment of healthy skin. Therefore, new options and new antibiotics are urgently needed and having that in mind our strategy is to use: i) antimicrobial peptides (AMP) to prevent or treat infection in the open wound; ii) collagen-inducing peptides (CBP) to induce fast healing; iii) and ionic liquids (IL) with intrinsic antimicrobial chemical permeation enhancement properties for an improved skin permeation. Through different combinations of these three types of building blocks, we aim to find a new class of active pharmaceutical ingredients suitable for topical application in the treatment of complicated skin infections. All the different conjugates designed and tested in vitro thus far will be presented. The most promising ones result from conjugation of CBP with IL, delivering a new type of conjugate with potent antibacterial, antifungal, and collagen-inducing effects on human dermal fibroblasts. Hence, these peptide-ionic liquid conjugates are promising leads towards the development of a topical formulation for the treatment of complicated skin infections.
- Repurposing conventional antimycobacterial drugs using ionic liquidsPublication . Bento, Clara M.; Silva, Tânia; Aguiar, Luísa; Teixeira, Cátia; Gomes, Paula; Ferraz, Ricardo; Gomes, Maria SaloméNontuberculous mycobacteria, namely the species belonging to the Mycobacterium avium complex, are highly infectious opportunistic pathogens, which incidence is increasing worldwide. Treating these infections is challenging, due to long duration, high toxicity, and low effectiveness of available drugs. It is therefore urgent to find new therapeutic strategies, including the repurposing of old drugs. Ionic liquids (ILs) are organic salts made by the combination of two molecules with opposite polarities, which are gaining attention in drug development. Combining the right ions, it is possible to create ILs that could avoid polymorphism and solubility issues presented by solid conventional drugs, improving their absorption and desired dissolution rate. Besides increasing the bioavailability, the main goals when formulating a new IL is keeping or improving the bioactivity and cytotoxicity properties of the parental drug(s). The aim of our work is to evaluate the ability of ILs based on conventional antimycobacterial drugs, like clofazimine, aminosalicylic acid, and fluoroquinolones, to inhibit the viability and growth of M. avium in axenic culture and inside macrophages.
- The emerging role of ionic liquid-based approaches for enhanced skin permeation of bioactive molecules: a snapshot of the past couple of yearsPublication . Gomes, Ana; Aguiar, Luísa; Ferraz, Ricardo; Teixeira, Cátia; Gomes, PaulaTopical and transdermal delivery systems are of undeniable significance and ubiquity in healthcare, to facilitate the delivery of active pharmaceutical ingredients, respectively, onto or across the skin to enter systemic circulation. From ancient ointments and potions to modern micro/nanotechnological devices, a variety of approaches has been explored over the ages to improve the skin permeation of diverse medicines and cosmetics. Amongst the latest investigational dermal permeation enhancers, ionic liquids have been gaining momentum, and recent years have been prolific in this regard. As such, this review offers an outline of current methods for enhancing percutaneous permeation, highlighting selected reports where ionic liquid-based approaches have been investigated for this purpose. Future perspectives on use of ionic liquids for topical delivery of bioactive peptides are also presented.