scholarly journals Mechanical penetration of β-lactam–resistant Gram-negative bacteria by programmable nanowires

2020 ◽  
Vol 6 (27) ◽  
pp. eabb9593 ◽  
Author(s):  
Lizhi Liu ◽  
Sheng Chen ◽  
Xu Zhang ◽  
Zhenjie Xue ◽  
Shengjie Cui ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Cell Envelope ◽  
Treatment Strategies ◽  
Physical Nature ◽  
Cell Stiffness ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Peptidoglycan Biosynthesis ◽  
Poor Understanding ◽  
Novel Treatment Strategies

β-Lactam–resistant (BLR) Gram-negative bacteria that are difficult or impossible to treat are causing a global health threat. However, the development of effective nanoantibiotics is limited by the poor understanding of changes in the physical nature of BLR Gram-negative bacteria. Here, we systematically explored the nanomechanical properties of a range of Gram-negative bacteria (Salmonella, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae) with different degrees of β-lactam resistance. Our observations indicated that the BLR bacteria had cell stiffness values almost 10× lower than that of β-lactam–susceptible bacteria, caused by reduced peptidoglycan biosynthesis. With the aid of numerical modeling and experimental measurements, we demonstrated that these stiffness findings can be used to develop programmable, stiffness-mediated antimicrobial nanowires that mechanically penetrate the BLR bacterial cell envelope. We anticipate that these stiffness-related findings will aid in the discovery and development of novel treatment strategies for BLR Gram-negative bacterial infections.

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

2020 ◽  
Vol 20 (3) ◽  
pp. 192-208 ◽  
Author(s):  
Talita Odriane Custodio Leite ◽  
Juliana Silva Novais ◽  
Beatriz Lima Cosenza de Carvalho ◽  
Vitor Francisco Ferreira ◽  
Leonardo Alves Miceli ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Mass Spectrometry Analysis ◽  
World Health ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dione Derivative ◽  
In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

scholarly journals The antimicrobial potential of cannabidiol

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mark A. T. Blaskovich ◽  
Angela M. Kavanagh ◽  
Alysha G. Elliott ◽  
Bing Zhang ◽  
Soumya Ramu ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Modern Medicine ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
New Class ◽  
Clostridioides Difficile ◽  
Excellent Activity ◽  
Induce Resistance ◽  
First Time

AbstractAntimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.

Fine structural observations of Desulfovibrio desulfuricans

1973 ◽  
Vol 19 (6) ◽  
pp. 753-756
Author(s):  
Terrence M. Hammill ◽  
Geno J. Germano
Keyword(s):  
Electron Microscopy ◽  
Cell Division ◽  
Cell Envelope ◽  
Desulfovibrio Desulfuricans ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Ultrathin Sections ◽  
Basal Apparatus ◽  
Specialized Region ◽  
Whole Mounts

Glutaraldehyde-fixed, platinum-carbon-shadowed whole mounts, and ultrathin sections of glutaraldehyde-OsO4-fixed cells of Desulfovibrio desulfuricans were observed by electron microscopy. The preparations demonstrated a typical Vibrio form with a single polar flagellum. The cell envelope and the formation of external blebs were shown to be similar to other gram-negative bacteria. The protoplast, apparently devoid of mesosomes or other membranous structures, was densely packed with ribosomes and contained a fibrous nucleoid. A specialized region near the flagellar end of the cell was commonly observed and termed the basal apparatus. Cell division appeared to be by constriction.

scholarly journals An overview of carbapenem, its resistance and therapeutic options for infections caused by carbapenem resistant bacteria

2020 ◽  
Vol 9 (9) ◽  
pp. 1454
Author(s):  
Hari P. Nepal ◽  
Rama Paudel
Keyword(s):  
Bacterial Infections ◽  
Carbapenem Resistance ◽  
Therapeutic Options ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Beta Lactam ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
Carbapenem Resistant ◽  
The World

Carbapenems are beta-lactam drugs that have broadest spectrum of activity. They are commonly used as the drugs of last resort to treat complicated bacterial infections. They bind to penicillin binding proteins (PBPs) and inhibit cell wall synthesis in bacteria. Important members that are in clinical use include doripenem, ertapenem, imipenem, and meropenem. Unlike other members, imipenem is hydrolyzed significantly by renal dehydropeptidase; therefore, it is administered together with an inhibitor of renal dehydropeptidase, cilastatin. Carbapenems are usually administered intravenously due to their low oral bioavailability. Most common side effects of these drugs include nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Increasing resistance to these antibiotics is being reported throughout the world and is posing a threat to public health.  Primary mechanisms of carbapenem resistance include expulsion of drug and inactivation of the drug by production of carbapenemases which may not only hydrolyze carbapenem, but also cephalosporin, penicillin, and aztreonam. Resistance especially among Gram negative bacteria is of much concern since there are only limited therapeutic options available for infections caused by carbapenem resistant Gram-negative bacterial pathogens. Commonly used drugs to treat such infections include polymyxins, fosfomycin and tigecycline.

scholarly journals Antibiotic transport kinetics in Gram-negative bacteria revealed via single-cell uptake analysis and mathematical modelling

2019 ◽  
Author(s):  
Jehangir Cama ◽  
Margaritis Voliotis ◽  
Jeremy Metz ◽  
Ashley Smith ◽  
Jari Iannucci ◽  
...  
Keyword(s):  
Rational Design ◽  
Cell Envelope ◽  
Time Lapse ◽  
Drug Accumulation ◽  
Cell Uptake ◽  
Gram Negative Bacteria ◽  
Label Free ◽  
Transport Pathways ◽  
Gram Negative ◽  
Accumulation Kinetics

AbstractThe double-membrane cell envelope of Gram-negative bacteria is a formidable barrier to intracellular antibiotic accumulation. A quantitative understanding of antibiotic transport in these cells is crucial for drug development, but this has proved elusive due to the complexity of the problem and a dearth of suitable investigative techniques. Here we combine microfluidics and time-lapse auto-fluorescence microscopy to quantify antibiotic uptake label-free in hundreds of individual Escherichia coli cells. By manipulating the microenvironment, we showed that drug (ofloxacin) accumulation is higher in growing versus non-growing cells. Using genetic knockouts, we provide the first direct evidence that growth phase is more important for drug accumulation than the presence or absence of individual transport pathways. We use our experimental results to inform a mathematical model that predicts drug accumulation kinetics in subcellular compartments. These novel experimental and theoretical results pave the way for the rational design of new Gram-negative antibiotics.

Diacylglycerol kinase A is essential for polymyxin resistance provided by EptA, MCR-1 and other lipid A phosphoethanolamine transferases.

2021 ◽  
Author(s):  
Alexandria B. Purcell ◽  
Bradley J. Voss ◽  
M. Stephen Trent
Keyword(s):  
Lipid A ◽  
Cell Envelope ◽  
Diacylglycerol Kinase ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Severe Reduction ◽  
Bacterial Fitness ◽  
Phosphoethanolamine Transferases ◽  
Kinase A

Gram-negative bacteria utilize glycerophospholipids (GPLs) as phospho-form donors to modify various surface structures. These modifications play important roles in bacterial fitness in diverse environments influencing cell motility, recognition by the host during infection, and antimicrobial resistance. A well-known example is the modification of the lipid A component of lipopolysaccharide by the phosphoethanolamine (pEtN) transferase EptA that utilizes phosphatidyethanoalmine (PE) as the phospho-form donor. Addition of pEtN to lipid A promotes resistance to cationic antimicrobial peptides (CAMPs), including the polymyxin antibiotics like colistin. A consequence of pEtN modification is the production of diacylglycerol (DAG) that must be recycled back into GPL synthesis via the diacylglycerol kinase A (DgkA). DgkA phosphorylates DAG forming phosphatidic acid, the precursor for GPL synthesis. Here we report that deletion of dgkA in polymyxin-resistant E. coli results in a severe reduction of pEtN modification and loss of antibiotic resistance. We demonstrate that inhibition of EptA is regulated post-transcriptionally and is not due to EptA degradation during DAG accumulation. We also show that the inhibition of lipid A modification by DAG is a conserved feature of different Gram-negative pEtN transferases. Altogether, our data suggests that inhibition of EptA activity during DAG accumulation likely prevents disruption of GPL synthesis helping to maintain cell envelope homeostasis.

scholarly journals How the assembly and protection of the bacterial cell envelope depend on cysteine residues

2020 ◽  
Vol 295 (34) ◽  
pp. 11984-11994 ◽  
Author(s):  
Jean-François Collet ◽  
Seung-Hyun Cho ◽  
Bogdan I. Iorga ◽  
Camille V. Goemans
Keyword(s):  
Amino Acid ◽  
Cell Envelope ◽  
Multilayered Structure ◽  
Cysteine Residues ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Amino Acid Residues ◽  
Gram Negative ◽  
Oxidative Inactivation ◽  
Peptidoglycan Cell Wall

The cell envelope of Gram-negative bacteria is a multilayered structure essential for bacterial viability; the peptidoglycan cell wall provides shape and osmotic protection to the cell, and the outer membrane serves as a permeability barrier against noxious compounds in the external environment. Assembling the envelope properly and maintaining its integrity are matters of life and death for bacteria. Our understanding of the mechanisms of envelope assembly and maintenance has increased tremendously over the past two decades. Here, we review the major achievements made during this time, giving central stage to the amino acid cysteine, one of the least abundant amino acid residues in proteins, whose unique chemical and physical properties often critically support biological processes. First, we review how cysteines contribute to envelope homeostasis by forming stabilizing disulfides in crucial bacterial assembly factors (LptD, BamA, and FtsN) and stress sensors (RcsF and NlpE). Second, we highlight the emerging role of enzymes that use cysteine residues to catalyze reactions that are necessary for proper envelope assembly, and we also explain how these enzymes are protected from oxidative inactivation. Finally, we suggest future areas of investigation, including a discussion of how cysteine residues could contribute to envelope homeostasis by functioning as redox switches. By highlighting the redox pathways that are active in the envelope of Escherichia coli, we provide a timely overview of the assembly of a cellular compartment that is the hallmark of Gram-negative bacteria.

scholarly journals Bacteria causing ventriculoperitoneal shunt infections in a Kenyan population

2015 ◽  
Vol 15 (2) ◽  
pp. 150-155 ◽  
Author(s):  
Naomi Ochieng' ◽  
Humphrey Okechi ◽  
Susan Ferson ◽  
A. Leland Albright
Keyword(s):  
Ventriculoperitoneal Shunt ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Infectious Complications ◽  
Gram Negative Bacteria ◽  
Shunt Insertion ◽  
Gram Negative ◽  
Western Literature ◽  
Sub Saharan ◽  
Few Data

OBJECT Ventriculoperitoneal shunt (VPS) infections are a major cause of morbidity and mortality in patients with hydrocephalus. Most data about these infections come from the Western literature. Few data about infecting organisms in Africa are available, yet knowledge of these organisms is important for the prevention and treatment of infectious complications. The purpose of this study was to determine the organisms cultured from infected shunts in a rural Kenyan hospital. METHODS The authors conducted a retrospective study of patients with VPS infections recorded in the neurosurgical database of BethanyKids at Kijabe Hospital between September 2010 and July 2012. RESULTS Among 53 VPS infections confirmed by culture, 68% occurred in patients who were younger than 6 months. Seventy-nine percent of the infections occurred within 2 months after shunt insertion. Only 51% of infections were caused by Staphylococcus species (Staphylococcus aureus 25%, other Staphylococcus species 26%), whereas 40% were caused by gram-negative bacteria. All S. aureus infections and 79% of other Staphylococcus infections were sensitive to cefazolin, but only 1 of 21 gram-negative bacteria was sensitive to it. The majority of gram-negative bacterial infections were multidrug resistant, but 17 of the 20 gram-negative bacteria were sensitive to meropenem. Gram-negative bacterial infections were associated with worse outcomes. CONCLUSIONS The high proportion of gram-negative infections differs from data in the Western literature, in which Staphylococcus epidermidis is by far the most common organism. Once a patient is diagnosed with a VPS infection in Kenya, immediate treatment is recommended to cover both gram-positive and gram-negative bacterial infections. Data from other Sub-Saharan countries are needed to determine if those countries have the same increased frequency of gram-negative infections.

scholarly journals Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S565-S575 ◽  
Author(s):  
Yohei Doi
Keyword(s):  
Bacterial Infections ◽  
Treatment Options ◽  
Clinical Development ◽  
Gram Negative Bacteria ◽  
First Line ◽  
Safe Alternative ◽  
New Agents ◽  
Gram Negative ◽  
Carbapenem Resistant

AbstractAntimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern due to the lack of effective and safe alternative treatment options. Carbapenem-resistant gram-negative bacteria of clinical relevance include the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and more recently, Stenotrophomonas maltophilia. Colistin and tigecycline have been used as first-line agents for the treatment of infections caused by these pathogens; however, there are uncertainties regarding their efficacy even when used in combination with other agents. More recently, several new agents with activity against certain carbapenem-resistant pathogens have been approved for clinical use or are reaching late-stage clinical development. They include ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, eravacycline, and cefiderocol. In addition, fosfomycin has been redeveloped in a new intravenous formulation. Data regarding the clinical efficacy of these new agents specific to infections caused by carbapenem-resistant pathogens are slowly emerging and appear to generally favor newer agents over previous best available therapy. As more treatment options become widely available for carbapenem-resistant gram-negative infections, the role of antimicrobial stewardship will become crucial in ensuring appropriate and rationale use of these new agents.

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