While the world is still attempting to recover from the damage caused by the broad spread of COVID-19, the monkeypox virus poses a new threat of becoming a global pandemic. Although the Monkeypox virus itself is not deadly and contagious as COVID-19, still every day, new patients case has been reported from many nations. Therefore, it will be no surprise if the world ever faces another global pandemic due to the lack of proper precautious steps. Recently, Machine learning (ML) has demonstrated huge potential in image-based diagnoses such as cancer detection, tumor cell identification, and COVID-19 patient detection. Therefore, a similar application can be adopted to diagnose the Monkeypox related disease as it infected the human skin, which image can be acquired and further used in diagnosing the disease. However, there is no publicly available Monkeypox dataset that can be used for training and experimenting the ML model development. Consequently, there is an immediate need to develop a dataset containing Monkeypox infected patients' images. Considering this opportunity, in this work, we introduce a newly developed "Monkeypox2022" dataset that is publicly available to use and can be obtained from our shared GitHub repository. The dataset is created by collecting images from multiple open-source and online portals that do not impose any restrictions on use, even for commercial purposes, hence giving a safer path to use and disseminate such data when constructing and deploying any type of ML models. Further, we propose and evaluate a modified VGG16 model, which includes two distinct studies: Study One and Two. Our exploratory computational results indicate that our suggested model can identify Monkeypox patients with an accuracy of 97 ± 1.8% (AUC = 97.2) and 88 ± 0.8% ( AUC = 0.867) for Study One and Two, respectively. Additionally, we explain our model's prediction and feature extraction utilizing Local
Antibiotic resistance poses an immediate and growing threat to human health. Multidrug efflux pumps are promising targets for overcoming antibiotic resistance with small-molecule therapeutics. Previously, we identified a diaminoquinoline acrylamide, NSC-33353, as a potent inhibitor of the AcrAB− TolC efflux pump in Escherichia coli. This inhibitor potentiates the antibacterial activities of novobiocin and erythromycin upon binding to the membrane fusion protein AcrA. It is also a substrate for efflux and lacks appreciable intrinsic antibacterial activity of its own in wild-type cells. Here, we have modified the substituents of the cinnamoyl group of NSC-33353, giving rise to analogs that retain the ability to inhibit efflux, lost the features of the efflux substrates, and gained antibacterial activity in wild-type cells. The replacement of the cinnamoyl group with naphthyl isosteres generated compounds that lack antibacterial activity but are both excellent efflux pump inhibitors and substrates. Surprisingly, these inhibitors potentiate the antibacterial activity of novobiocin but not erythromycin. Surface plasmon resonance experiments and molecular docking suggest that the replacement of the cinnamoyl group with naphthyl shifts the affinity of the compounds away from AcrA to the AcrB transporter, making them better efflux substrates and changing their mechanism of inhibition. These results provide new insights into the duality of efflux substrate/inhibitor features in chemical scaffolds that will facilitate the development of new efflux pump inhibitors.
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Optimization of compound permeation into Gram-negative bacteria is one of the most challenging tasks in the development of antibacterial agents. Two permeability barriers�the passive diffusion barrier of the outer membrane (OM) and active drug efflux�act synergistically to protect cells from the antibacterial action of compounds. In Escherichia coli (E. coli) and relatives, these two barriers sieve compounds based on different physicochemical properties that are defined by their interactions with OM porins and efflux pumps, respectively. In this study, we critically tested the hypothesis that the best substrates and inhibitors of efflux pumps are compounds that can effectively permeate the OM and are available at relatively high concentrations in the periplasm. For this purpose, we filtered a large subset of the ZINC15 database of commercially available compounds for compounds containing a primary amine, a chemical feature known to facilitate the uptake through E. coli general porins. The assembled library was screened by ensemble docking to AcrA, the periplasmic component of the AcrAB-TolC efflux pump, followed by experimental testing of the top predicted binders for antibacterial activities, efflux recognition, and inhibition. We found that the filtered primary amine library is a rich source of compounds with effluxinhibiting activities and identified efflux pump inhibitors with novel chemical scaffolds effective against E. coli AcrAB-TolC and efflux pumps of multidrug-resistant clinical isolates of Acinetobacter baumannii. However, primary amines are not required for the recognition of compounds by efflux pumps and their efflux-inhibitory activities.
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