Search

According to WHO, to combat the resistant strains, new effective anti-microbial agents are needed on an urgent basis and global researchers should focus their efforts and discovery programs on developing them against antibiotic-resistant pathogens or priority pathogens like ESKAPE. In this context, Cationic antimicrobial peptides (AMPs) are being explored extensively as promising next-generation antimicrobials due to their broad range, fast kinetics and multifunctional role. Despite recent advances, it is still a daunting challenge to identify and design a potent AMP with no cytotoxicity, but with broad specific antimicrobial activity, stability and efficacy under in vivo conditions in a cost-effective and robust manner. In this work, as a proof of concept, we designed novel potent AMPs using artificial intelligence based in silico programs. Shortlisted peptide sequences were synthesized using the fmoc chemistry approach, assessed their antimicrobial activity, cell selectivity, mode of action and in vivo efficacy using a series of experiments. The synthesized peptide analogues demonstrated their antimicrobial activity (MIC in the range of 2.5–80 μM) against bacteria. The identified potential lead molecules showed antibacterial activity in physiological conditions with no signs of cytotoxicity. We further tested the antimicrobial activity of peptide analogues for treating wounds infected with Pseudomonas aeruginosa in the mice burn wound model. In drug-development programs, the identification of lead antimicrobial agents is always challenging and involves screening a large number of molecules which is time-consuming and expensive. This work demonstrates the utility of artificial intelligence based in silico analysis programs in discovering novel antimicrobial agents in an economical, robust way.

Formononetin (FNT) has limited application due to poor water solubility and substantial phase II metabolism. In the present study, we used phospholipid complex (PC) containing FNT and UDP-glucuronosyltransferase (UGT1A1) inhibitor piperine (PIP) to overcome FNT limitations. We characterized and compared both FNT-PC and FNT-PIP-PC complexes. Our data showed both groups improved FNT water solubility and oil-water partition coefficient. NMR, DSC, and SEM were performed to identify the interaction and the geometrical nature of complex. When compared, FNT-PIP-PC released more FNT in in vitro release and permeation through Caco-2 monolayer than FNT-PC and pure FNT. In vitro data was consistent with the in vivo pharmacokinetic profile that showed increased, Cmax and AUC(0-24) by 7.16 and 23.33-fold and 29.65 and 23.33-fold at 5 and 10 mg/kg in FNT-PIP-PC, compared to pure FNT. Additionally, co-treatment of PIP and FNT improved in vitro pharmacological action in dexamethasone-induced osteoporosis. Thus, our study showed addition of PIP in FNT-PC further increases FNT water solubility and protects it from phase II metabolism, leading to enhanced bioavailability with improved pharmacological activity. [ABSTRACT FROM AUTHOR]

The implementation of the laser sintering for inkjet-printed nanoparticles and metal organic decomposition (MOD) inks on a flexible polymeric film has been analyzed in detail. A novel approach by implementing, next to a commonly 3.2 mm diameter spot laser optic, a line laser optic with a laser beam area of 2 mm × 80 mm, demonstrates the high potential of selective laser sintering to proceed towards a fast and efficient sintering methodology in printed electronics. In this work, a multiplicity of laser parameters, primary the laser speed and the laser power, have been altered systematically to identify an optimal process window for each ink and to convert the dried and non-conductive patterns into conductive and functional silver structures. For each ink, as well as for the two laser optics, a suitable laser parameter set has been found, where a conductivity without any damage to the substrate or silver layer could be achieved. In doing so, the margin of the laser speed for both optics is ranging in between 50 mm/s and 100 mm/s, which is compatible with common inkjet printing speeds and facilitates an in-line laser sintering approach. Considering the laser power, the typical parameter range for the spot laser lays in between 10 W and 50 W, whereas for the line optics the full laser power of 200 W had to be applied. One of the nanoparticle silver inks exhibits, especially for the line laser optic, a conductivity of up to 2.22 × 107 S‧m−1, corresponding to 36% of bulk silver within a few seconds of sintering duration. Both laser sintering approaches together present a remarkable facility to use the laser either as a digital tool for sintering of defined areas by means of a spot beam or to efficiently sinter larger areas by means of a line beam. With this, the utilization of a laser sintering methodology was successfully validated as a promising approach for converting a variety of inkjet-printed silver patterns on a flexible polymeric substrate into functionalized conductive silver layers for applications in the field of printed electronics. [ABSTRACT FROM AUTHOR]

The Apicomplexa phylum encompasses numerous obligate intracellular parasites, some associated with severe implications for human health, including Plasmodium, Cryptosporidium, and Toxoplasma gondii. The iron-sulfur cluster [Fe-S] biogenesis ISC pathway, localized within the mitochondrion or mitosome of these parasites, is vital for parasite survival and development. Previous work on T. gondii and Plasmodium falciparum provided insights into the mechanisms of [Fe-S] biogenesis within this phylum, while the transporter linking mitochondria-generated [Fe-S] with the cytosolic [Fe-S] assembly (CIA) pathway remained elusive. This critical step is catalyzed by a well-conserved ABC transporter, termed ATM1 in yeast, ATM3 in plants and ABCB7 in mammals. Here, we identify and characterize this transporter in two clinically relevant Apicomplexa. We demonstrate that depletion of TgATM1 does not specifically impair mitochondrial metabolism. Instead, proteomic analyses reveal that TgATM1 expression levels inversely correlate with the abundance of proteins that participate in the transfer of [Fe-S] to cytosolic proteins at the outer mitochondrial membrane. Further insights into the role of TgATM1 are gained through functional complementation with the well-characterized yeast homolog. Biochemical characterization of PfATM1 confirms its role as a functional ABC transporter, modulated by oxidized glutathione (GSSG) and [4Fe-4S]. Author summary: The Apicomplexa phylum includes harmful parasites like Plasmodium falciparum and Toxoplasma gondii, posing significant threats to human health. Understanding their survival mechanisms is crucial for developing effective treatments. Here, our focus is on iron-sulfur cluster [Fe-S] synthesis pathways found in the mitochondrion and cytosol, essential for the function of many enzymes. Although the transporter responsible for moving sulfur-containing compounds from mitochondria to the cytosol is known in other organisms, it remains unidentified in apicomplexans. Our study identifies PfATM1 and TgATM1 as critical transporters in the mitochondrial membrane of these parasites. Downregulation or overexpression of TgATM1 levels do not hinder mitochondrial functions but affect the level of other proteins, suspected to donate [Fe-S] to cytosolic proteins. We further confirm the transporter's role by rescuing TgATM1 depleted parasites with the yeast homolog ScATM1. Additionally, we identify glutathione-coordinated [4Fe-4S] as a probable substrate for PfATM1. These findings provide valuable insights into how parasites manage essential resources, potentially opening new avenues for targeted drug development. [ABSTRACT FROM AUTHOR]