The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt ...Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.
Colletotrichum fructicola, a fungal pathogen that causes bitter rot disease in pears, has recently emerged in Eastern Asia and caused enormous economic losses and crop penalties. For this reason, new ...strategies for the management of bitter rot disease are greatly needed and can have a great impact on the field. In this regard, our research group recently reported that p-aminobenzoic acid (pABA), which was found in the secretions of rhizobacterium Lysobacter antibioticus OH13, showed a broad spectrum of antifungal activities. Following this project, the antifungal mode of action of pABA has been elucidated in this work indicating that pABA affects the fungal cell cycle of C. fructicola by inhibiting septation during cell division. pABA stability and diffusion screening revealed that pABA degrades after 15 days and is able to cross the pear skin into the external parts of the mesocarp. In vivo studies demonstrated that pABA shows high curative ability against the infection of C. fructicola in pears. To show the efficacy of OH13 for the biocontrol of bitter rot disease, cultures of OH13 containing 379.4 mg/L pABA were sprayed on inoculated pears, significantly reducing the symptoms of the pathogen.
Inhibition of plasminogen activator inhibitor (PAI)-1 is useful to treat several disorders including thrombosis. An inhibitor of PAI-1 (TM5275) was newly identified by an extensive study of ...structure-activity relationship based on a lead compound (TM5007) which was obtained through virtual screening by docking simulations. Its antithrombotic efficacy and adverse effects were tested in vivo in rats and nonhuman primates (cynomolgus monkey). TM5275, administered orally in rats (1 to 10 mg/kg), has an antithrombotic effect equivalent to that of ticlopidine (500 mg/kg) in an arterialvenous shunt thrombosis model and to that of clopidogrel (3 mg/kg) in a ferric chloride-treated carotid artery thrombosis model. TM5275 does not modify activated partial thromboplastin time and prothrombin time or platelet activity and does not prolong bleeding time. Combined with tissue plasminogen activator, TM5275 improves the latter's therapeutic efficacy and reduces its adverse effect. Administered to a monkey model of photochemical induced arterial thrombosis, TM5275 (10 mg/kg) has the same antithrombotic effect as clopidogrel (10 mg/kg), without enhanced bleeding. This study documents the antithrombotic benefits of a novel, more powerful, PAI-1 inhibitor in rats and, for the first time, in nonhuman primates. These effects are obtained without adverse effect on bleeding time.
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•Pyrolysis treatment of Prussian blue analogues to prepare defect-rich carbon based Fe-Mn bimetallic oxides.•Lattice oxygen was the main reactive site for ABEE degradation.•Transition ...of pyridinic N and sacrifice of lattice oxygen were responsible for enhanced catalytic performance.•Degradation pathway included electrophilic and radical addition, hydrogen abstraction reaction and diazotization.
Meeting with severe environmental problems, highly efficient, environmental friendly and multiple reusable catalysts are demanding to develop. In this work, carbon based bimetallic oxides with oxygen vacancies were prepared toward peroxymonosulfate (PMS) activation for 4-aminobenzoic acid ethyl ester (ABEE) degradation. Among different molar ratios of ferrous ions and manganese ion, Fe1Mn1-Fe NC appeared optimum catalytic performance. The degradation of ABEE should contain free radical pathway and non-free radical pathway. All of sulfate radical, hydroxyl radical, superoxide radical and singlet oxygen were responsible for efficient degradation and mineralization of ABEE. Lattice oxygen was the main reactive site for ABEE degradation. Electron transport provided good synergistic redox reaction between Fe and Mn and promoted lattice oxygen released. New proposed pathway for ABEE degradation included electrophilic and radical addition, hydrogen abstraction reaction and diazotization. This work is expected to provide rational design of bimetallic materials with oxygen vacancy for in-situ environmental remediation.
Topical formulations are not always suitable to deliver active ingredients to large areas of skin. Thus, in this study, we aimed to develop an oral formulation for skin tissue targeting with a high ...bioavailability using liquid crystal (LC) dispersions comprising cubosomes of a mal-absorptive model compound, p-amino benzoic acid (PABA), which is an active element in cosmeceuticals, dietary supplements and skin disorder medicines. The bioavailability and skin concentration of PABA were investigated after oral administration in rats. The effect of the remaining amount of the LC formulation in the stomach on the pharmacokinetic profiles of orally administered PABA was evaluated. The skin permeation and concentration of PABA were also investigated using an in vitro permeation experiment. As a result, the bioavailability of PABA was significantly improved by administration of PABA–LC formulations compared with PABA solution alone, although the effect was greatly influenced by the type of LC-forming lipids. The in vitro skin permeation study showed that the PABA concentration in the skin when applied from the dermis side was higher than when applied from the epidermis side. These findings suggested that oral administration advantageously supports skin targeting, and oral LC formulations could be a promising material in cosmeceutical, dietary and clinical fields.
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Surface plasmon resonance (SPR) bridges photonics and photoelectrochemistry by providing an effective interaction between absorption and confinement of light to surface electrons of plasmonic metal ...nanostructures (PMNs). SPR enhances the Raman intensity enormously in surface-enhanced Raman spectroscopy (SERS) and leads to the plasmon-mediated chemical reaction on the surface of nanostructured metal electrodes. To observe variations in chemical reactivity and selectivity, we studied the SPR photoelectrochemical reactions of para-aminobenzoic acid (PABA) on nanostructured gold electrodes. The head-to-tail coupling product “4-(4-imino-2,5-cyclohexadien-1-ylidene)aminobenzoic acid (ICBA)” and the head-to-head coupling product p,p′–azodibenzoate (ADBA) were obtained from PABA adsorbed on PMN-modified gold electrodes. In particular, under acidic and neutral conditions, ICBA was obtained as the main product, and ADBA was obtained as the minor product. At the same time, under basic conditions, ADBA was obtained as the major product, and ICBA was obtained as the minor product. We have also provided sufficient evidence for the oxidation of the tail-to-tail coupling reaction product that occurred in a nonaqueous medium rather than in an aqueous medium. The above finding was validated by the cyclic voltammetry, SERS, and theoretical calculation results of possible reaction intermediates, namely, 4-aminophenlylenediamine, 4-hydroxyphenlylenediamine, and benzidine. The theoretical adsorption model and experimental results indicated that PABA has been adsorbed as para-aminobenzoate on the gold cluster in a bidentate configuration. This work offers a new view toward the modulation of selective surface catalytic coupling reactions on PMN, which benefits the hot carrier transfer efficiency at photoelectrochemical interfaces.
Natural products are a major source of new antibiotics. Here we utilize biosynthetic instructions contained within metagenome‐derived congener biosynthetic gene clusters (BGCs) to guide the synthesis ...of improved antibiotic analogues. Albicidin and cystobactamid are the first members of a new class of broad‐spectrum ρ‐aminobenzoic acid (PABA)‐based antibiotics. Our search for PABA‐specific adenylation domain sequences in soil metagenomes revealed that BGCs in this family are common in nature. Twelve BGCs that were bio‐informatically predicted to encode six new congeners were recovered from soil metagenomic libraries. Synthesis of these six predicted structures led to the identification of potent antibiotics with changes in their spectrum of activity and the ability to circumvent resistance conferred by endopeptidase cleavage enzymes.
Biosynthetic instructions contained within congener biosynthetic gene clusters (BGCs) have been used to guide the synthesis of improved antibiotic analogues. ρ‐Aminobenzoic acid encoding BGCs cloned from soil metagenomes have guided the synthesis of albicidin and cystobactamid analogues that show increased potency, different spectra of activity, as well as the ability to circumvent resistance conferred by endopeptidase cleavage enzymes.
•Amino-defective UiO-66 was prepared in a one-step synthesis process using 4-amino benzoic acid.•Adding 4-aminobenzoic acid enhanced the porosity and formation of amino groups as new CO2 adsorption ...sites.•The defect degree was controlled by 4-aminobenzoic acid concentration.•Amino-defective UiO-66 showed improved CO2 adsorption capacity and CO2/N2 selectivity.
UiO-66(Zr), one of the Zr-based metal–organic frameworks (MOFs), is a potential adsorbent for gas separation owing to its large surface area, easily tunable pore structure, and high chemical/thermal stability. Nevertheless, its CO2 adsorption amount is somewhat modest in comparison to that of various MOFs. In this study, 4-aminobenzoic acid (PABA) as amino-defective linker was mixed to terephthalic acid at various compositions in a one-step synthesis of UiO-66(Zr) framework. This new restructuring strategy produced defective UiO-66(Zr) with enhanced porosity owing to the missing-linker defects, simultaneously formed –NH2 groups in the framework, leading to the improvement of the CO2 capture capacity. At 298 K and 100 kPa, the defective UiO-66 modified with 10% PABA exhibited the highest CO2 uptake capacity of ~ 2.47 mmol g−1 and ideal adsorbed solution theory (IAST)-based CO2/N2 selectivity of ~ 46, which surpass many other CO2 benchmark adsorbents. This opens a new perspective for developing defective UiO-66(Zr) adsorbent contained amine functional groups, which can improve CO2 separation performance.
•4-ABA is used as a multifunctional electrolyte additive in cells.•4-ABA facilitates the desolvation of Li+ and increases the Li+ transference number.•Preferential oxidation of 4-ABA helps to build a ...protective CEI film.•CEI film suppresses electrolyte decomposition and prevents NCA destruction.
The application of Li metal anode in high energy density batteries is hindered by uncontrolled dendrites growth and rapid capacity decline. In this study, 4-aminobenzoic acid (4-ABA) is used as a multifunctional electrolyte additive to effectively stabilise Li anode and extend the cycling life of LiNi0.8Co0.15Al0.05O2 (NCA) cathode in carbonate electrolyte. It is found that 4-ABA facilitates the desolvation of Li+ and increases the Li+ transference number, leading to an increase in Li+ flux on the surface of the Li anode, and finally the growth of Li dendrites is inhibited. The cycling performance of Li||Li symmetric cell is extended from < 400 h to more than 600 h at 1 mA cm−2 with a capacity of 1 mAh cm−2. For the NCA cathode, 4-ABA is involved in the formation of a thin and uniform cathode electrolyte interphase (CEI) layer, which is conducive to inhibiting the corrosion of electrolyte on NCA cathode and reducing the dissolution of the transition metals Ni and Co. Thus, the electrochemical performances of the Li||NCA cell with the electrolyte containing 0.5% 4-ABA are significantly improved. In particular, the discharge capacity of the cells with the electrolyte containing 0.5% 4-ABA are still 164.9 and 150.7 mAh g−1compared to only 126.3 and 116.0 mAh/g for the cells with the baseline electrolyte after 200 cycles at 1C and 5C. This study provides a simple and effective strategy for improving the electrochemical performances of Li anodes and NCA cathodes by optimising the electrolyte.
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