Plant defensins are a large family of proteins, most of which have antifungal activity against a broad spectrum of fungi. However, little is known about how they exert their activity. The mechanisms ...of action of only a few members of the family have been investigated and, in most cases, there are still a number of unknowns.
Plant defensins are a large family of proteins, most of which have antifungal activity against a broad spectrum of fungi. However, little is known about how they exert their activity. The mechanisms of action of only a few members of the family have been investigated and, in most cases, there are still a number of unknowns. To gain a better understanding of the antifungal mechanisms of a set of four defensins, NaD1, DmAMP1, NbD6, and SBI6, we screened a pooled collection of the nonessential gene deletion set of
Saccharomyces cerevisiae
. Strains with increased or decreased ability to survive defensin treatment were identified based on the relative abundance of the strain-specific barcode as determined by MiSeq next-generation sequencing. Analysis of the functions of genes that are deleted in strains with differential growth in the presence of defensin provides insight into the mechanism of action. The screen identified a novel role for the vacuole in the mechanisms of action for defensins NbD6 and SBI6. The effect of these defensins on vacuoles was further confirmed by using confocal microscopy in both
S. cerevisiae
and the cereal pathogen
Fusarium graminearum
. These results demonstrate the utility of this screening method to identify novel mechanisms of action for plant defensins.
Probiotics are live beneficial bacteria introduced into the gastrointestinal tract through food or water, promoting good health by enhancing the internal microbial balance. Probiotic microbes produce ...bacteriocins, siderophores, lysozymes, proteases, and hydrogen peroxides, inhibiting the growth of harmful pathogens. Such beneficial bacteria also produce many enzymes such as amylase enzyme by Aeromonas spp., Bacillus subtilis, Bacteridaceae, Clostridium spp., Lactobacillus plantarum, and Staphylococcus sp., and protease and cellulase enzymes by B. subtilis, L. plantarum, and Staphylococcus sp. In aquaculture, probiotics confer several benefits and play important roles in improving growth performances, disease resistance, immunity, health status, intestinal epithelial barrier integrity, gut microbiome, and water quality. In addition, the practical application of probiotics in aquaculture diets could minimize antibiotic side effects. Promoting these feed additives for fish would help to improve their productive performance and feed utilization and, therefore, boost fish production and safeguard human health. This review provides updated information regarding definitions, sources of bacterial probiotics, probiotic use in fish diets against pathogenic bacteria, mechanisms of action, beneficial aspects, and potential applications of probiotics in fish. It is anticipated that these will be of significant value for nutritionists, agricultural engineers, researchers, pharmacists, scientists, pharmaceutical industries, and veterinarians.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antimicrobial resistance (AMR) is an ever-growing public health problem worldwide. The low rate of antibiotic discovery coupled with the rapid spread of drug-resistant bacterial pathogens is causing ...a global health crisis. To facilitate the drug discovery processes, we present a large-scale study of reference antibiotic challenge bacterial transcriptome profiles, which included 37 antibiotics across 6 mechanisms of actions (MOAs) and provide an economical approach to aid in antimicrobial dereplication in the discovery process. We demonstrate that classical MOAs can be sorted based upon the magnitude of gene expression profiles despite some overlap in the secondary effects of antibiotic exposures across MOAs. Additionally, using gene subsets, we were able to subdivide broad MOA classes into subMOAs. Furthermore, we provide a biomarker gene set that can be used to classify most antimicrobial challenges according to their canonical MOA. We also demonstrate the ability of this rapid MOA diagnostic tool to predict and classify the expression profiles of pure compounds and crude extracts to their expression profile-associated MOA class.
Highlights ► Diet is a major source of OCP exposure for the general population. ► OCPs exposure can induce enzymes for hormones and toxicants metabolisms. ► OCPs exposure are suspected to be ...associated to endocrine function disruption. ► Possible toxicity mechanisms are hormone disruption, oxidative stress or epigenetic. ► Understanding of these mechanisms helps to improve public health interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against
Leishmania
share this origin.
Drug repurposing ...affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against
Leishmania
share this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets in
Leishmania
were poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline on
Leishmania infantum
, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on the bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress in
L. infantum
promastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as a shortage of intracellular amino acids used as metabolic fuel by
Leishmania
. Sertraline killed
Leishmania
through a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy.
New antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate ...antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of
covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for
-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.
Andrographis paniculata (A. paniculata) is a medicinal plant traditionally used as anti-inflammation and anti-bacteria herb. Andrographolide, the major active component of A. paniculata, exhibits ...diverse pharmacological activities, including anti-inflammation, anti-cancer, anti-obesity, anti-diabetes, and other activities. In this article, we comprehensively review the therapeutic potential of A. paniculata and andrographolide focusing on the mechanisms of action and clinical application. We systemically discuss the structure-activity relationship of andrographolide and derivatives. Despite the various pharmacological activities and formula of A. paniculata and andrographolide, we propose further development of more structural derivatives of andrographolide with reduced toxicity and increased therapeutic efficacy is still needed for the clinical application of this ancient mighty herb and its major component.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
9.
Pyrrolomycins Are Potent Natural Protonophores Valderrama, Katherine; Pradel, Elizabeth; Firsov, Alexander M ...
Antimicrobial agents and chemotherapy,
10/2019, Volume:
63, Issue:
10
Journal Article
Peer reviewed
Open access
The escalating burden of antibiotic drug resistance necessitates research into novel classes of antibiotics and their mechanism of action. Pyrrolomycins are a family of potent natural product ...antibiotics with nanomolar activity against Gram-positive bacteria, yet with an elusive mechanism of action. In this work, we dissect the apparent Gram-positive specific activity of pyrrolomycins and show that Gram-negative bacteria are equally sensitive to pyrrolomycins when drug efflux transporters are removed and that albumin in medium plays a large role in pyrrolomycin activity. The selection of resistant mutants allowed for the characterization and validation of a number of mechanisms of resistance to pyrrolomycins in both
and an
Δ
mutant, all of which appear to affect compound penetration rather than being target associated. Imaging of the impact of pyrrolomycin on the
Δ
mutant using scanning electron microscopy showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and an electrophysiological technique with an artificial bilayer lipid membrane, it was demonstrated that pyrrolomycins C and D are very potent membrane-depolarizing agents, an order of magnitude more active than conventional carbonyl cyanide
-chlorophenylhydrazone (CCCP), specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the until-now-elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria.
Phenotypic screening identified an arylsulfonamide compound with activity against Trypanosoma cruzi, the causative agent of Chagas' disease. Comprehensive mode of action studies revealed that this ...compound primarily targets the T. cruzi proteasome, binding at the interface between β4 and β5 subunits that catalyze chymotrypsin-like activity. A mutation in the β5 subunit of the proteasome was associated with resistance to compound 1, while overexpression of this mutated subunit also reduced susceptibility to compound 1. Further genetically engineered and
-selected clones resistant to proteasome inhibitors known to bind at the β4/β5 interface were cross-resistant to compound 1. Ubiquitinated proteins were additionally found to accumulate in compound 1-treated epimastigotes. Finally, thermal proteome profiling identified malic enzyme as a secondary target of compound 1, although malic enzyme inhibition was not found to drive potency. These studies identify a novel pharmacophore capable of inhibiting the T. cruzi proteasome that may be exploitable for anti-chagasic drug discovery.
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