Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

Preeclampsia: a gestational cardiorenal syndrome.

It is generally accepted today that there are two different types of preeclampsia: an early-onset or placental type and a late-onset or maternal type. In the latent phase, the first one presents with a low output/high resistance circulation eventually leading in the late second or early third trimester to an intense and acutely aggravating systemic disorder with an important impact on maternal and neonatal mortality and morbidity; the other type presents initially as a high volume/low resistance circulation, gradually evolving to a state of circulatory decompensation usually in the later stages of pregnancy, with a less severe impact on maternal and neonatal outcome. For both processes, numerous dysfunctions of the heart, kidneys, arteries, veins and interconnecting systems are reported, most of them presenting earlier and more severely in early- than in late-onset preeclampsia; however, some very specific dysfunctions exist for either type. Experimental, clinical and epidemiological observations before, during and after pregnancy are consistent with gestation-induced worsening of subclinical pre-existing chronic cardiovascular dysfunction in early-onset preeclampsia, and thus sharing the pathophysiology of cardiorenal syndrome type II, and with acute volume overload decompensation of the maternal circulation in late-onset preeclampsia, thus sharing the pathophysiology of cardiorenal syndrome type 1. Cardiorenal syndrome type V is consistent with the process of preeclampsia superimposed upon clinical cardiovascular and/or renal disease, alone or as part of a systemic disorder. This review focuses on the specific differences in haemodynamic dysfunctions between the two types of preeclampsia, with special emphasis on the interorgan interactions between heart and kidneys, introducing the theoretical concept that the pathophysiological processes of preeclampsia can be regarded as the gestational manifestations of cardiorenal syndromes

Silica Materials for Medical Applications

The two main applications of silica-based materials in medicine and biotechnology, i.e. for bone-repairing devices and for drug delivery systems, are presented and discussed. The influence of the structure and chemical composition in the final characteristics and properties of every silica-based material is also shown as a function of the both applications presented. The adequate combination of the synthesis techniques, template systems and additives leads to the development of materials that merge the bioactive behavior with the drug carrier ability. These systems could be excellent candidates as materials for the development of devices for tissue engineering

Large-scale unit commitment under uncertainty: an updated literature survey

The Unit Commitment problem in energy management aims at finding the optimal production schedule of a set of generation units, while meeting various system-wide constraints. It has always been a large-scale, non-convex, difficult problem, especially in view of the fact that, due to operational requirements, it has to be solved in an unreasonably small time for its size. Recently, growing renewable energy shares have strongly increased the level of uncertainty in the system, making the (ideal) Unit Commitment model a large-scale, non-convex and uncertain (stochastic, robust, chance-constrained) program. We provide a survey of the literature on methods for the Uncertain Unit Commitment problem, in all its variants. We start with a review of the main contributions on solution methods for the deterministic versions of the problem, focussing on those based on mathematical programming techniques that are more relevant for the uncertain versions of the problem. We then present and categorize the approaches to the latter, while providing entry points to the relevant literature on optimization under uncertainty. This is an updated version of the paper "Large-scale Unit Commitment under uncertainty: a literature survey" that appeared in 4OR 13(2), 115--171 (2015); this version has over 170 more citations, most of which appeared in the last three years, proving how fast the literature on uncertain Unit Commitment evolves, and therefore the interest in this subject

Development of novel ultrashort antimicrobial peptide nanoparticles with potent antimicrobial and antibiofilm activities against multidrug-resistant bacteria

Ammar Almaaytah,1 Gubran Khalil Mohammed,1 Ahmad Abualhaijaa,2 Qosay Al-Balas3 1Department of Pharmaceutical Technology, Faculty of Pharmacy, 2Department of Applied Biological Sciences, Faculty of Science and Arts, 3Department of Medicinal Chemistry, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Abstract: Conventional antibiotics are facing strong microbial resistance that has recently reached critical levels. This situation is leading to significantly reduced therapeutic potential of a huge proportion of antimicrobial agents currently used in clinical settings. Antimicrobial peptides (AMPs) could provide the medical community with an alternative strategy to traditional antibiotics for combating microbial resistance. However, the development of AMPs into clinically useful antibiotics is hampered by their relatively low stability, toxicity, and high manufacturing costs. In this study, a novel in-house-designed potent ultrashort AMP named RBRBR was encapsulated into chitosan-based nanoparticles (CS-NPs) based on the ionotropic gelation method. The encapsulation efficacy reported for RBRBR into CS-NPs was 51.33%, with a loading capacity of 10.17%. The release kinetics of RBRBR from the nanocarrier exhibited slow release followed by progressive linear release for 14 days. The antibacterial kinetics of RBRBR-CS-NPs was tested against four strains of Staphylococcus aureus for 4 days, and the developed RBRBR-CS-NPs exhibited a 3-log decrease in the number of colonies when compared to CS-NP and a 5-log decrease when compared to control bacteria. The encapsulated peptide NP formulation managed to limit the toxicity of the free peptide against both mammalian cells and human erythrocytes. Additionally, the peptide NPs demonstrated up to 98% inhibition of biofilm formation when tested against biofilm-forming bacteria. Loading RBRBR into CS-NPs could represent an innovative approach to develop delivery systems based on NP technology for achieving potent antimicrobial effects against multidrug-resistant and biofilm-forming bacteria, with negligible systemic toxicity and reduced synthetic costs, thereby overcoming the obstructions to clinical development of AMPs. Keywords: ultrashort antimicrobial peptides, nanoparticles, drug delivery, antibiofil

Synthesis, antimicrobial and in vitro antitumor activities of a series of 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives

Nizar M Mhaidat,1,2 Mousa Al-Smadi,3 Fouad Al-Momani,4 Karem H Alzoubi,1 Iman Mansi,2 Qosay Al-Balas5 1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 2Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, 3Department of Applied Chemical Sciences, 4Department of Applied Biological Sciences, Faculty of Science and Arts, 5Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, JordanAbstract: Three derivatives of substituted 1,2,3-thia- or 1,2,3-selenadiazole (4a–c) were prepared and characterized by different chemical techniques. These compounds were evaluated for their antimicrobial and antitumor activities. Compounds 4a (propenoxide derivative), 4b (carbaldehyde derivative), and 4c (benzene derivative) were active against the yeast-like fungi Candida albicans. Compound 4a was active against gram-negative Escherichia coli, and compound 4c was active against the gram-positive Staphylococcus aureus. For the antitumor activity, both compounds 4b and 4c were active against all tested tumor cell lines, namely, SW480, HCT116, C32, MV3, HMT3522, and MCF-7. The activity of compound 4c was greater than that of compound 4b and more than that of the reference antitumor 5-flourouracil against the SW480, HCT116, and MCF-7 tumor cell lines. In conclusion, a number of the prepared 1,2,3-thia- or 1,2,3-selenadiazole compounds showed promising antifungal, antibacterial, and in vitro antitumor activities. Further investigations are required to explore the mechanism by which active compound are inducing their cytotoxicity. Keywords: thiadiazole, selenadiazole, cell lines, antimicrobial activit

Hybridization and antibiotic synergism as a tool for reducing the cytotoxicity of antimicrobial peptides

Ammar Almaaytah,1 Mohammed T Qaoud,1 Ahmad Abualhaijaa,2 Qosay Al-Balas,3 Karem H Alzoubi4 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Applied Biological Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Medicinal Chemistry, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 4Department Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Introduction: As the development of new antimicrobial agents faces a historical decline, the issue of bacterial drug resistance has become a serious dilemma that threatens the human population worldwide. Antimicrobial peptides (AMPs) represent an attractive and a promising class of antimicrobial agents. Aim: The hybridization of AMPs aimed at merging two individual active fragments of native peptides to generate a new AMP with altered physicochemical properties that translate into an enhanced safety profile. Materials and methods: In this study, we have rationally designed a new hybrid peptide via combining two individual α-helical fragments of both BMAP-27 and OP-145. The resultant peptide, was evaluated for its antimicrobial and antibiofilm activity against a range of microbial strains. The resultant peptide was also evaluated for its toxicity against mammalian cells using hemolytic and anti proliferative assays. Results: The antimicrobial activity of H4 revealed that the peptide is displaying a broad spectrum of activity against both Gram-positive and Gram-negative bacteria including standard and multidrug-resistant bacterial strains in the range of 2.5–25 μM. The new hybrid peptide displayed potent activity in eradicating biofilm-forming cells, and the reported minimum biofilm eradication concentrations were equal to the minimum inhibitory concentration values reported for planktonic cells. Additionally, H4 exhibited reduced toxicity profiles against eukaryotic cells. Combining H4 peptide with conventional antibiotics has led to a dramatic enhancement of the antimicrobial activity of both agents with synergistic or additive outcomes. Conclusion: Overall, this study indicates the success of both the hybridization and synergism strategy in developing AMPs as potential antimicrobial therapeutics with reduced toxicity profiles that could be efficiently employed to eradicate resistant bacterial strains and enhance the selectivity and toxicity profiles of native AMPs. Keywords: antimicrobial peptides, peptide hybridization, antibiotic synergism, biofilms, antimicrobial resistanc

Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides

Ammar Almaaytah,1 Ya’u Ajingi,2 Ahmad Abualhaijaa,2 Shadi Tarazi,2 Nizar Alshar’i,3 Qosay Al-Balas3 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Applied Biological Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Medicinal Chemistry, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Abstract: The rise of multidrug-resistant bacteria is causing a serious threat to the world’s human population. Recent reports have identified bacterial strains displaying pan drug resistance against antibiotics and generating fears among medical health specialists that humanity is on the dawn of entering a post-antibiotics era. Global research is currently focused on expanding the lifetime of current antibiotics and the development of new antimicrobial agents to tackle the problem of antimicrobial resistance. In the present study, we designed a novel consensus peptide named “Pepcon” through peptide consensus sequence determination among members of a highly homologous group of scorpion antimicrobial peptides. Members of this group were found to possess moderate antimicrobial activity with significant toxicity against mammalian cells. The aim of our design method was to generate a novel peptide with an enhanced antimicrobial potency and selectivity against microbial rather than mammalian cells. The results of our study revealed that the consensus peptide displayed potent antibacterial activities against a broad range of Gram-positive and Gram-negative bacteria. Our membrane permeation studies displayed that the peptide efficiently induced membrane damage and consequently led to cell death through the process of cell lysis. The microbial DNA binding assay of the peptide was found to be very weak suggesting that the peptide is not targeting the microbial DNA. Pepcon induced minimal cytotoxicity at the antimicrobial concentrations as the hemolytic activity was found to be zero at the minimal inhibitory concentrations (MICs). The results of our study demonstrate that the consensus peptide design strategy is efficient in generating peptides. Keywords: peptide, scorpion, venom, peptide design, antimicrobial peptides, consensus sequenc