scholarly journals A polymeric approach toward resistance-resistant antimicrobial agent with dual-selective mechanisms of action

2021 ◽  
Vol 7 (5) ◽  
pp. eabc9917
Author(s):  
Silei Bai ◽  
Jianxue Wang ◽  
Kailing Yang ◽  
Cailing Zhou ◽  
Yangfan Xu ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mechanisms Of Action ◽  
Model Systems ◽  
General Strategy ◽  
Antimicrobial Polymers ◽  
Bacterial Dna ◽  
Bacterial Membranes ◽  
Severe Infections ◽  
Multiple Drugs ◽  
Resistance Rates

Antibiotic resistance is now a major threat to human health, and one approach to combating this threat is to develop resistance-resistant antibiotics. Synthetic antimicrobial polymers are generally resistance resistant, having good activity with low resistance rates but usually with low therapeutic indices. Here, we report our solution to this problem by introducing dual-selective mechanisms of action to a short amidine-rich polymer, which can simultaneously disrupt bacterial membranes and bind to bacterial DNA. The oligoamidine shows unobservable resistance generation but high therapeutic indices against many bacterial types, such as ESKAPE strains and clinical isolates resistant to multiple drugs, including colistin. The oligomer exhibited excellent effectiveness in various model systems, killing extracellular or intracellular bacteria in the presence of mammalian cells, removing all bacteria from Caenorhabditis elegans, and rescuing mice with severe infections. This “dual mechanisms of action” approach may be a general strategy for future development of antimicrobial polymers.

scholarly journals Antifungal Activities of Antineoplastic Agents:Saccharomyces cerevisiae as a Model System To Study Drug Action

1999 ◽  
Vol 12 (4) ◽  
pp. 583-611 ◽  
Author(s):  
Maria E. Cardenas ◽  
M. Cristina Cruz ◽  
Maurizio Del Poeta ◽  
Namjin Chung ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Kinase Inhibitor ◽  
Genetic Model ◽  
Fungal Infections ◽  
Study Drug ◽  
Drug Action ◽  
Mechanisms Of Action ◽  
Model Systems ◽  
Screening Tools ◽  
Sphingolipid Metabolism

SUMMARY Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated. Possibly as a consequence, many natural-product toxins that have antimicrobial activity are also toxic to mammalian cells. While this makes it difficult to discover antifungal agents without toxic side effects, it also has enabled detailed studies of drug action in simple genetic model systems. We review here studies on the antifungal actions of antineoplasmic agents. Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism. In general, these natural products inhibit target proteins conserved from microorganisms to humans. These studies highlight the potential of microorganisms as screening tools to elucidate the mechanisms of action of novel pharmacological agents with unique effects against specific mammalian cell types, including neoplastic cells. In addition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for which few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.

Autophagy Modulators and Neuroinflammation

2020 ◽  
Vol 27 (6) ◽  
pp. 955-982 ◽  
Author(s):  
Kyoung Sang Cho ◽  
Jang Ho Lee ◽  
Jeiwon Cho ◽  
Guang-Ho Cha ◽  
Gyun Jee Song
Keyword(s):  
Neurodegenerative Disorders ◽  
Neurological Disorders ◽  
Mammalian Cells ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Scientific Interest ◽  
Therapeutic Tools ◽  
Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

scholarly journals Interaction of Acinetobacter baumannii with Human Serum Albumin: Does the Host Determines the Outcome?

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 833
Author(s):  
Camila Pimentel ◽  
Casin Le ◽  
Marisel R. Tuttobene ◽  
Tomas Subils ◽  
Krisztina M. Papp-Wallace ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Human Serum Albumin ◽  
Quorum Sensing ◽  
Serum Albumin ◽  
Human Serum ◽  
Acinetobacter Baumannii ◽  
Biofilm Formation ◽  
Model Systems ◽  
Expression Levels ◽  
Multiple Drugs

Acinetobacter baumannii has become a serious threat to human health due to its extreme antibiotic resistance, environmental persistence, and capacity to survive within the host. Two A. baumannii strains, A118 and AB5075, commonly used as model systems, and three carbapenem-resistant strains, which are becoming ever more dangerous due to the multiple drugs they can resist, were exposed to 3.5% human serum albumin (HSA) and human serum (HS) to evaluate their response with respect to antimicrobial resistance, biofilm formation, and quorum sensing, all features responsible for increasing survival and persistence in the environment and human body. Expression levels of antibiotic resistance genes were modified differently when examined in different strains. The cmlA gene was upregulated or downregulated in conditions of exposure to 3.5% HSA or HS depending on the strain. Expression levels of pbp1 and pbp3 tended to be increased by the presence of HSA and HS, but the effect was not seen in all strains. A. baumannii A118 growing in the presence of HS did not experience increased expression of these genes. Aminoglycoside-modifying enzymes were also expressed at higher or lower levels in the presence of HSA or HS. Still, the response was not uniform; in some cases, expression was enhanced, and in other cases, it was tapered. While A. baumannii AB5075 became more susceptible to rifampicin in the presence of 3.5% HSA or HS, strain A118 did not show any changes. Expression of arr2, a gene involved in resistance to rifampicin present in A. baumannii AMA16, was expressed at higher levels when HS was present in the culture medium. HSA and HS reduced biofilm formation and production of N-Acyl Homoserine Lactone, a compound intimately associated with quorum sensing. In conclusion, HSA, the main component of HS, stimulates a variety of adaptative responses in infecting A. baumannii strains.

scholarly journals Antimicrobial Peptides: Mechanisms of Action and Resistance

2016 ◽  
Vol 96 (3) ◽  
pp. 254-260 ◽  
Author(s):  
B. Bechinger ◽  
S.-U. Gorr
Keyword(s):  
Cell Wall ◽  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Rare Event ◽  
Mechanisms Of Action ◽  
Current Evidence ◽  
Aggregation State ◽  
Host Defense Peptides ◽  
Bacterial Membranes

More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide’s structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

scholarly journals Diffusion in the aqueous compartment.

1984 ◽  
Vol 99 (1) ◽  
pp. 180s-187s ◽  
Author(s):  
A M Mastro ◽  
A D Keith
Keyword(s):  
Rotational Motion ◽  
Spin Label ◽  
Mammalian Cells ◽  
Translational Motion ◽  
Diffusion Constant ◽  
Rotational Correlation Time ◽  
Model Systems ◽  
Quiescent Cells ◽  
Spin Resonance ◽  
In Cells

Measurements of diffusion of molecules in cells can provide information about cytoplasmic viscosity and structure. In a series of studies electron-spin resonance was used to measure the diffusion of a small spin label in the aqueous cytoplasm of mammalian cells. Translational and rotational motion were determined from the same spectra. Based on measurements made in model systems, it was hypothesized that calculations of the apparent viscosity of the cytoplasm from both rotational and translational motion would distinguish between the effects of viscosity and structure on diffusion. The diffusion constant measured in several cell lines averaged 3.3 X 10(-6) cm2/s. It was greater in growing cells and in cells treated with cytochalasin B than in quiescent cells. The viscosity of the cytoplasm calculated from the translational diffusion constant or the rotational correlation time was 2.0-3.0 centipoise, about two to three times that of the spin label in water. Therefore, over the dimensions measured by the technique, 50-100 A, solvent viscosity appears to be the major determinant of particle movement in cells under physiologic conditions. However, when cells were subjected to hypertonic conditions, the translational motion of the spin label decreased threefold, whereas the rotational motion changed by less than 20%. These data suggest that the decrease in cell volume under hypertonic conditions is accompanied by an increase in cytoplasmic barriers and a decrease in the space between existing cytoplasmic components without a significant increase in viscosity in the aqueous phase. In addition, a comparison of reported diffusion values of a variety of molecules in water and in cells indicates that cytoplasmic structure plays an important role in the diffusion of proteins such as bovine serum albumin.

Cyclic AMP-dependent protein kinase regulates sensitivity of cells to multiple drugs

1987 ◽  
Vol 7 (9) ◽  
pp. 3098-3106
Author(s):  
I Abraham ◽  
R J Hunter ◽  
K E Sampson ◽  
S Smith ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Mammalian Cells ◽  
Multiple Drug Resistance ◽  
Regulatory Subunit ◽  
Parent Cell ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Antimitotic Drug ◽  
Multiple Drugs

The isolation of mutant cell lines affecting the activity of cyclic AMP (cAMP)-dependent protein kinase (PK-A) has made it possible to determine the function of this kinase in mammalian cells. We found that both a CHO cell mutant with a defective regulatory subunit (RI) for PK-A and a transfectant cell line expressing the same mutant kinase were sensitive to multiple drugs, including puromycin, adriamycin, actinomycin D, and some antimitotic drugs. The mutant and transfectant cells, after treatment with a concentration of the antimitotic drug colcemid that had no marked effect on the wild-type parent cell, had a severely disrupted microtubule network. The phenotype of hypersensitivity to the antimitotic drug colcemid was used to select revertants of the transfectant and the original mutant. These revertants simultaneously regained normal multiple drug resistance and cAMP sensitivity, thus establishing that the characteristics of colcemid sensitivity and cAMP resistance are linked. Four revertants of the transfectant reverted because of loss or rearrangement of the transfected mutant RI gene. These revertants, as well as one revertant selected from the original mutant, had PK-A activities equal to or higher than that of the parent. In these genetic studies, in which linkage of expression of a PK-A mutation with drug sensitivity is demonstrated, it was established that the PK-A system is involved in regulating resistance of mammalian cells to multiple drugs.

The Influence of Bacteria on Animal Metamorphosis

2020 ◽  
Vol 74 (1) ◽  
pp. 137-158
Author(s):  
Giselle S. Cavalcanti ◽  
Amanda T. Alker ◽  
Nathalie Delherbe ◽  
Kyle E. Malter ◽  
Nicholas J. Shikuma
Keyword(s):  
Mechanisms Of Action ◽  
Model Systems ◽  
Marine Animals ◽  
Hydroides Elegans ◽  
Animal Development ◽  
Ship Hulls ◽  
Coral Reef Ecosystems ◽  
Environmental Bacteria ◽  
Animal Interaction ◽  
Developmental Decision

The swimming larvae of many marine animals identify a location on the seafloor to settle and undergo metamorphosis based on the presence of specific surface-bound bacteria. While bacteria-stimulated metamorphosis underpins processes such as the fouling of ship hulls, animal development in aquaculture, and the recruitment of new animals to coral reef ecosystems, little is known about the mechanisms governing this microbe-animal interaction. Here we review what is known and what we hope to learn about how bacteria and the factors they produce stimulate animal metamorphosis. With a few emerging model systems, including the tubeworm Hydroides elegans, corals, and the hydrozoan Hydractinia, we have begun to identify bacterial cues that stimulate animal metamorphosis and test hypotheses addressing their mechanisms of action. By understanding the mechanisms by which bacteria promote animal metamorphosis, we begin to illustrate how, and explore why, the developmental decision of metamorphosis relies on cues from environmental bacteria.

scholarly journals Down-modulation of Type 1 Interferon Responses by Receptor Cross-competition for a Shared Jak Kinase

2001 ◽  
Vol 276 (50) ◽  
pp. 47004-47012 ◽  
Author(s):  
Elisabetta Dondi ◽  
Els Pattyn ◽  
Georges Lutfalla ◽  
Xaveer Van Ostade ◽  
Gilles Uzé ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Transcriptional Response ◽  
Erythropoietin Receptor ◽  
Cellular Systems ◽  
Janus Kinase ◽  
Model Systems ◽  
Interleukin 12 ◽  
Interferon Α ◽  
Receptor Complexes

In contrast to the large number of class I and II cytokine receptors, only four Janus kinase (Jak) proteins are expressed in mammalian cells, implying the shared use of these kinases by many different receptor complexes. Consequently, if receptor numbers exceed the amount of available Jak, cross-interference patterns can be expected. We have engineered two model cellular systems expressing two different exogenous Tyk2-interacting receptors. A receptor chimera was generated wherein the extracellular part of the interferon type 1 receptor (Ifnar1) component of the interferon-α/β receptor is replaced by the equivalent domain of the erythropoietin receptor. Despite Tyk2 activation, erythropoietin treatment of cells expressing this erythropoietin receptor/Ifnar1 chimera did not evoke any detectable IFN-type response. However, a dose-dependent interference with signal transduction via the endogenous Ifnar complex was found for STAT1, STAT2, STAT3, Tyk2, and Jak1 activation, for gene induction, and for antiviral activity. In a similar approach, cells expressing the β1 chain of the interleukin-12 receptor showed a reduced transcriptional response to IFN-α as well as reduced STAT and kinase activation. In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference.

scholarly journals Cyclic AMP-dependent protein kinase regulates sensitivity of cells to multiple drugs.

1987 ◽  
Vol 7 (9) ◽  
pp. 3098-3106 ◽  
Author(s):  
I Abraham ◽  
R J Hunter ◽  
K E Sampson ◽  
S Smith ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Mammalian Cells ◽  
Multiple Drug Resistance ◽  
Regulatory Subunit ◽  
Parent Cell ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Antimitotic Drug ◽  
Multiple Drugs

The isolation of mutant cell lines affecting the activity of cyclic AMP (cAMP)-dependent protein kinase (PK-A) has made it possible to determine the function of this kinase in mammalian cells. We found that both a CHO cell mutant with a defective regulatory subunit (RI) for PK-A and a transfectant cell line expressing the same mutant kinase were sensitive to multiple drugs, including puromycin, adriamycin, actinomycin D, and some antimitotic drugs. The mutant and transfectant cells, after treatment with a concentration of the antimitotic drug colcemid that had no marked effect on the wild-type parent cell, had a severely disrupted microtubule network. The phenotype of hypersensitivity to the antimitotic drug colcemid was used to select revertants of the transfectant and the original mutant. These revertants simultaneously regained normal multiple drug resistance and cAMP sensitivity, thus establishing that the characteristics of colcemid sensitivity and cAMP resistance are linked. Four revertants of the transfectant reverted because of loss or rearrangement of the transfected mutant RI gene. These revertants, as well as one revertant selected from the original mutant, had PK-A activities equal to or higher than that of the parent. In these genetic studies, in which linkage of expression of a PK-A mutation with drug sensitivity is demonstrated, it was established that the PK-A system is involved in regulating resistance of mammalian cells to multiple drugs.

scholarly journals Sterol Properties Required for Microdomain Formation: From Model Systems to Living Yeast and Mammalian Cells

2012 ◽  
Vol 102 (3) ◽  
pp. 298a
Author(s):  
André E.P. Bastos ◽  
Alena Khmelinskaia ◽  
Silvia Scolari ◽  
Rui Malhó ◽  
Andreas Herrmann ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Model Systems
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