Correction to Antibiotic Adjuvants: Make Antibiotics Great Again!

The ability of 6-(aryl)methylidene penicillin-based sulfones 1−7 to repurpose β-lactam antibiotics activity with bacterial species that carry carbapenem-hydrolyzing class D βlactamases (OXA-23, OXA-24/40 and OXA-48), as well as with class A (TEM-1, CTX-M-2) and class C (CMY-2, DHA-1) enzymes, is reported. The combinations imipenem/3 and imipenem/4 restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing A. baumannii strains (1 μg mL −1) and also provided good results for OXA-48 carbapenemase-producing K. pneumoniae strains (4 μg mL −1). Compounds 2−6 in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in E. coli strains carrying class C (CMY-2 and DHA-1) and class A (TEM-1 and CTX-M-2) β-lactamase enzymes, respectively. Kinetic and inhibition studies with the OXA-24/40 enzyme, protein mass spectrometry analysis and docking studies allowed us to gain an insight into the inhibition mechanism and the experimentally observed differences between the ligands.

Acta Pharmaceutica Hungarica, 2020

Introduction: The emergence of multidrug-resistant bacterial strains is a severe global health issue, which is worsened by the inability of new antibiotics. Virulence inhibition is one of the novel strategies that have been proposed to combat bacterial pathogens more effectively, without the risk of exerting selection pressure on these microorganisms. Inhibition of bacterial cell-cell communication (quorum sensing; QS) is a promising approach however, rapid and cost-effective screening for compounds with QS-inhibitory activity is not yet well-established. Aims: The aim of the present study is to determine the ideal experimental conditions for the disk-diffusion based QS-inhibitory assay with the most frequently used QS-signal molecule-producing and reporter strains. Methods: In our study, the effects of growth characteristics, incubation time, temperature and the used culture media were studied on the used bacterial strains and results of the disk-diffusion based QS-inhibitory assay...

2021

Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity a...

Journal of medicinal chemistry, 2016

Selective inhibitors of bromodomain-containing protein 9 (BRD9) may have therapeutic potential in the treatment of human malignancies and inflammatory diseases. A selective small molecule inhibitor that is well tolerated and has proper pharmacokinetic properties is required to explore the function of BRD9 in diseases. BI-9564 (2) is a cell permeable and noncytotoxic BRD9 inhibitor provided to the scientific community to explore BRD9 biology and determine its potential as a drug target.

Therapeutic options to treat multidrug resistant bacteria, especially when present in biofilms, are limited due to their high levels of antibiotic resistance. Here, we report the anti-biofilm and immunomodulatory activities of the host defense peptide (HDP)-mimicking β-peptide polymer (20:80 Bu:DM) and investigated its activity in vivo. The polymer outperformed antibiotics in the removal and reduction of the viability of established biofilms, achieving a maximum activity of around 80% reduction in viability. Interestingly the polymer also exhibited HDP-like immunomodulation in inducing chemokines and anti-inflammatory cytokines and suppressing lipopolysaccharide-induced proinflammatory cytokines. When tested in a murine, high-density skin infection model using P. aeruginosa LESB58, the polymer was effective in diminishing abscess size and reducing bacterial load. This study demonstrates the dual functionality of HDP-mimicking β-peptide polymers in inhibiting biofilms and modulating innate immunity, as well as reducing tissue dermonecrosis.

European Regional Science Association, 2001

Abstract * National and local "economic development programs" -programs that provide assistance to individual businesses with tax or financial subsidies, or special public services, in order to increase local jobs or improve local businesses' competitiveness -have become prominent and controversial. The paper illustrates the basic principles of development agencies that are not invariable and specific structures, rather "ideal-typical" structures that assume particular aspects only referring to a variety of local society answers'. In this sense, a tool as the enterprise incubator could foster the growth of entrepreneurs in regional contexts with a low level of entrepreneurial attitude. The definition of a model of incubator, through the analysis of a specific case study, the Israeli technological incubators, whose outline conditions, resources, vocations, obligations and their incidence on policies of entrepreneurships promotion in Israel are identified, help us to outline factors of success, direct and induced effects on regional contexts, possible new relations introduced among actors, also in a new informational economy perspective. The local context characters, both at human and social capital level and at institutional and infrastructure levels, become decisive factors for productive choices, overtaking sometimes the national level to link directly to global networks. In this way, it seems inevitable a transformation of both the aims and the organisation in a changing context. The role of development agencies has moved from promoting the local demand to structure involved in elaborating solutions in the socio-economic field.

Luxor International journal of archaeological studies, 2024

Swords were important weapons for the Romans, who used multiple types during the Roman era, whether inspired by Greek and Spanish swords, or otherwise. Their sizes, shapes, and names varied. These included short, long, and honorary swords. The sword generally consists of the blade, hilt, and sheath. There were also swords for ordinary soldiers and other swords for senior officers, commanders and emperors, as well as the use of daggers that sometimes replaced swords. This research deals with the hilt of a sword that was preserved in the Egyptian Museum in Cairo and was later transferred to the Greco-Roman Museum in Alexandria. This hilt is decorated with a bronze eagle head. The research aims to determine the sword of this hilt through a descriptive and comparative analytical study of this hilt, which necessarily requires identifying the different types of swords and their periods of use, while answering many questions that arise about interpreting the symbolism of the design of the end of the handle in the form of an eagle's head. And the origin of using birds to decorate hilts of swords, specifically the eagle? And the significance of this motif for Rome? Was it a usual decoration for swords used by ordinary infantry? or not? Was the bearer of this sword an ordinary soldier, a military header, or an emperor?

This article follows the alchemical political economy of Edward Gibbon Wakefield for whom Kāi Tahu whenua served as a laboratory. Wakefield's clever formula for the transubstantiation of an incendiary social situation in Britain into new terrain for capital was designed to secure the transplantation of English economic and social relations to the colonies to ensure the persistence of a landless class compelled to sell their labour for wages. Ingeniously, the transport of that labour to the colonies was to be paid for by the market in land in the new colony: Kāi Tahu would be made to fund their own colonisation. I track the fate of capital's settler dream for ready land and labour as it was brought into being by the New Zealand Company, subsequently taken over by the Crown, and as it continues into our present. The argument is divided into two parts. The first is the classical moment of primitive accumulation, clearing people from the land to provide a market in land and labour, 'legal' dispossession, and commodification. The second is the more recent continuation of the initial processes of dispossession and commodification as these assert themselves in processes of redress and as they are expressed in the corporatisation of Ngāi Tahu.