scholarly journals Intravenous Immunoglobulin for Treating Bacterial Infections: One More Mechanism of Action

2019 ◽  
Author(s):  
Teiji Sawa ◽  
Mao Kinoshita ◽  
Keita Inoue ◽  
Junya Ohara ◽  
Kiyoshi Moriyama
Keyword(s):  
Bacterial Infections ◽  
Bacterial Toxin ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Secretion Systems ◽  
Gram Negative ◽  
Drug Resistant Bacteria ◽  
Toxin Secretion ◽  
Dependent Cell ◽  
V Antigen

The mechanisms underlying the effects of γ-globulin therapy for bacterial infections are thought to involve bacterial cell lysis via complement activation, phagocytosis via bacterial opsonization, toxin neutralization, and antibody-dependent cell-mediated cytotoxicity. Nevertheless, recent advances in the study of pathogenicity in gram-negative bacteria have raised the possibility of an association between γ-globulin and bacterial toxin secretion. Over time, new toxin secretion systems like the type III secretion system have been discovered in many pathogenic gram-negative bacteria. With this system, the bacterial toxins are directly injected into the cytoplasm of the target cell through a special secretory apparatus without any exposure to the extracellular environment and, therefore, with no opportunity for antibodies to neutralize the toxin. However, because antibodies against the V-antigen, which is located on the needle-shaped tip of the bacterial secretion apparatus, can inhibit toxin translocation, this raises the hope that the toxin might be susceptible to antibody targeting. Because multi-drug resistant bacteria are now prevalent, inhibiting this secretion mechanism is attractive as an alternative or adjunctive therapy against lethal bacterial infections. Thus, it would not be unreasonable to define the blocking effect of anti-V-antigen antibodies as the fifth mechanism for immunoglobulin action against bacterial infections.

scholarly journals Immunoglobulin for Treating Bacterial Infections: One More Mechanism of Action

Antibodies ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 52 ◽  
Author(s):  
Sawa ◽  
Kinoshita ◽  
Inoue ◽  
Ohara ◽  
Moriyama
Keyword(s):  
Bacterial Infections ◽  
Bacterial Toxin ◽  
Resistant Bacteria ◽  
Attractive Alternative ◽  
Gram Negative Bacteria ◽  
Secretion Systems ◽  
Gram Negative ◽  
Drug Resistant Bacteria ◽  
Toxin Secretion ◽  
V Antigen

The mechanisms underlying the effects of immunoglobulins on bacterial infections are thought to involve bacterial cell lysis via complement activation, phagocytosis via bacterial opsonization, toxin neutralization, and antibody-dependent cell-mediated cytotoxicity. Nevertheless, recent advances in the study of the pathogenicity of Gram-negative bacteria have raised the possibility of an association between immunoglobulin and bacterial toxin secretion. Over time, new toxin secretion systems like the type III secretion system have been discovered in many pathogenic Gram-negative bacteria. With this system, the bacterial toxins are directly injected into the cytoplasm of the target cell through a special secretory apparatus without any exposure to the extracellular environment, and therefore with no opportunity for antibodies to neutralize the toxin. However, antibodies against the V-antigen, which is located on the needle-shaped tip of the bacterial secretion apparatus, can inhibit toxin translocation, thus raising the hope that the toxin may be susceptible to antibody targeting. Because multi-drug resistant bacteria are now prevalent, inhibiting this secretion mechanism is an attractive alternative or adjunctive therapy against lethal bacterial infections. Thus, it is not unreasonable to define the blocking effect of anti-V-antigen antibodies as the fifth mechanism for immunoglobulin action against bacterial infections.

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 Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R againstEscherichia coli

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3168 ◽  
Author(s):  
Diana Machado ◽  
Laura Fernandes ◽  
Sofia S. Costa ◽  
Rolando Cannalire ◽  
Giuseppe Manfroni ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Bacterial Infections ◽  
Efflux Pump ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Gram Negative ◽  
E Coli ◽  
Efflux Pump Inhibitors

Efflux pump inhibitors are of great interest since their use as adjuvants of bacterial chemotherapy can increase the intracellular concentrations of the antibiotics and assist in the battle against the rising of antibiotic-resistant bacteria. In this work, we have described the mode of action of the 2-phenylquinoline efflux inhibitor (4-(2-(piperazin-1-yl)ethoxy)-2-(4-propoxyphenyl) quinolone – PQQ4R), againstEscherichia coli,by studding its efflux inhibitory ability, its synergistic activity in combination with antibiotics, and compared its effects with the inhibitors phenyl-arginine-β-naphthylamide (PAβN) and chlorpromazine (CPZ). The results showed that PQQ4R acts synergistically, in a concentration dependent manner, with antibiotics known to be subject to efflux inE. colireducing their MIC in correlation with the inhibition of their efflux. Real-time fluorometry assays demonstrated that PQQ4R at sub-inhibitory concentrations promote the intracellular accumulation of ethidium bromide inhibiting its efflux similarly to PAβN or CPZ, well-known and described efflux pump inhibitors for Gram-negative bacteria and whose clinical usage is limited by their levels of toxicity at clinical and bacteriological effective concentrations. The time-kill studies showed that PQQ4R, at bactericidal concentrations, has a rapid antimicrobial activity associated with a fast decrease of the intracellular ATP levels. The results also indicated that the mode of action of PQQ4R involves the destabilization of theE. coliinner membrane potential and ATP production impairment, ultimately leading to efflux pump inhibition by interference with the energy required by the efflux systems. At bactericidal concentrations, membrane permeabilization increases and finally ATP is totally depleted leading to cell death. Since drug resistance mediated by the activity of efflux pumps depends largely on the proton motive force (PMF), dissipaters of PMF such as PQQ4R, can be regarded as future adjuvants of conventional therapy againstE. coliand other Gram-negative bacteria, especially their multidrug resistant forms. Their major limitation is the high toxicity for human cells at the concentrations needed to be effective against bacteria. Their future molecular optimization to improve the efflux inhibitory properties and reduce relative toxicity will optimize their potential for clinical usage against multi-drug resistant bacterial infections due to efflux.

scholarly journals Infections with Carbapenem-Resistant Gram-Negative Bacteria are a Serious Problem Among Critically Ill Children: A Single-Centre Retrospective Study

Pathogens ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 69 ◽  
Author(s):  
Fatih Aygun ◽  
Fatma Deniz Aygun ◽  
Fatih Varol ◽  
Cansu Durak ◽  
Haluk Çokuğraş ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Critically Ill ◽  
Bacterial Infections ◽  
Invasive Mechanical Ventilation ◽  
Critically Ill Children ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Culture Positive

Children in paediatric intensive care units (PICUs) are vulnerable to infections because invasive devices are frequently used during their admission. We aimed to determine the prevalence, associated factors, and prognosis of infections in our PICU. This retrospective study evaluated culture results from 477 paediatric patients who were treated in the PICU between January 2014 and March 2019. Ninety patients (18.9%) had bacterial infections, with gram-negative bacteria being the predominant infectious agents. Culture-positive patients were younger than culture-negative patients, and age was related to mortality and various clinical factors. Culture-positive bacterial infections in the PICU were associated with increased use of invasive mechanical ventilation (odds ratio(OR); 2.254), red blood cell (RBC) transfusions (OR:2.624), and inotropic drugs (OR:2.262). Carbapenem resistance was found in approximately one-third of gram-negative bacteria, and was most common in tracheal aspirate specimens and cases involving Klebsiella spp. Total parenteral nutrition was a significant risk factor (OR:5.870). Positive blood culture results were associated with poorer patient survival than other culture results. These findings indicate that infections, especially those involving carbapenem-resistant bacteria, are an important issue when treating critically ill children.

scholarly journals Bacteriocins, Antimicrobial Peptides from Bacterial Origin: Overview of Their Biology and Their Impact against Multidrug-Resistant Bacteria

2020 ◽  
Vol 8 (5) ◽  
pp. 639 ◽  
Author(s):  
Alexis Simons ◽  
Kamel Alhanout ◽  
Raphaël E. Duval
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Further Development

Currently, the emergence and ongoing dissemination of antimicrobial resistance among bacteria are critical health and economic issue, leading to increased rates of morbidity and mortality related to bacterial infections. Research and development for new antimicrobial agents is currently needed to overcome this problem. Among the different approaches studied, bacteriocins seem to be a promising possibility. These molecules are peptides naturally synthesized by ribosomes, produced by both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB), which will allow these bacteriocin producers to survive in highly competitive polymicrobial environment. Bacteriocins exhibit antimicrobial activity with variable spectrum depending on the peptide, which may target several bacteria. Already used in some areas such as agro-food, bacteriocins may be considered as interesting candidates for further development as antimicrobial agents used in health contexts, particularly considering the issue of antimicrobial resistance. The aim of this review is to present an updated global report on the biology of bacteriocins produced by GPB and GNB, as well as their antibacterial activity against relevant bacterial pathogens, and especially against multidrug-resistant bacteria.

scholarly journals Cathelicidin Antimicrobial Peptides with Reduced Activation of Toll-Like Receptor Signaling Have Potent Bactericidal Activity against Colistin-Resistant Bacteria

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Cheng Kao ◽  
Xiaoyan Lin ◽  
Guanghui Yi ◽  
Yunliang Zhang ◽  
Dean A. Rowe-Magnus ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Bactericidal Activity ◽  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Human Cells ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Human Red Blood Cells ◽  
Minor Injuries

ABSTRACT The world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria. IMPORTANCE Cathelicidins are antimicrobial peptides that can also increase inflammatory responses. This combination of activities can cause complications in the treatment of bacterial infections despite the pressing need for new antimicrobials. We have identified cathelicidins with decreased activation of inflammatory responses. The peptides kill Gram-negative bacteria at low micromolar concentrations by binding to and perturbing the integrity of the bacterial membrane. The peptides were also engineered to further decrease lysis of human red blood cells. The peptides have activities comparable to those of the polymyxins, a class of antibiotics to which plasmid-borne resistance is rapidly spreading and can kill colistin-resistant bacteria. These peptides are promising candidates for the development of novel antibacterial agents.

scholarly journals Multiple Mechanisms of the Synthesized Antimicrobial Peptide TS against Gram-Negative Bacteria for High Efficacy Antibacterial Action In Vivo

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 60
Author(s):  
Rui Zhang ◽  
Xiaobo Fan ◽  
Xinglu Jiang ◽  
Mingyuan Zou ◽  
Han Xiao ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Divalent Cations ◽  
Resistant Bacteria ◽  
Antibacterial Drug ◽  
Gram Negative Bacteria ◽  
Gram Negative

The emergence of drug-resistant bacteria emphasizes the urgent need for novel antibiotics. The antimicrobial peptide TS shows extensive antibacterial activity in vitro and in vivo, especially in gram-negative bacteria; however, its antibacterial mechanism is unclear. Here, we find that TS without hemolytic activity disrupts the integrity of the outer bacterial cell membrane by displacing divalent cations and competitively binding lipopolysaccharides. In addition, the antimicrobial peptide TS can inhibit and kill E. coli by disintegrating the bacteria from within by interacting with bacterial DNA. Thus, antimicrobial peptide TS’s multiple antibacterial mechanisms may not easily induce bacterial resistance, suggesting use as an antibacterial drug to be for combating bacterial infections in the future.

scholarly journals Lysophosphatidylcholine Potentiates Antibacterial Activity of Polymyxin B

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Jitender Yadav ◽  
Sana Ismaeel ◽  
Ayub Qadri
Keyword(s):  
Antibacterial Activity ◽  
Polymyxin B ◽  
Resistant Bacteria ◽  
Bacterial Membrane ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Drug Resistant Bacteria

ABSTRACT Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of Salmonella and at least two other Gram-negative bacteria in vitro. This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.

scholarly journals Escherichia Coli Isolate From Hospital Sewage Is Carrying blaNDM-1 and blaoxa-10

2021 ◽  
Author(s):  
Zimeng Hu ◽  
Weiye Chen ◽  
Genglin Guo ◽  
Chen Dong ◽  
Yun Shen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Drug Resistance ◽  
Hospital Environment ◽  
Multi Drug Resistance ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Drug Resistant Bacteria ◽  
Hospital Sewage

Abstract Carbapenems, as the “last line of defense” against gram-negative bacteria, are increasingly being challenged by drug-resistant bacteria, especially in Enterobacteriaceae. In this study, a carbapenems resistant gram-negative bacterium, named AH001, was isolated from hospital sewage, and modified Hoge test confirmed this bacterium can produce carbapenemase. Further analysis revealed that this bacterium is multi-drug resistance, which against additional seven antibiotics. Whole-genome sequencing and analysis showed that AH001 could not be classified by existing MLST, and its serotype couldn’t be distinguished among O9, O89 or O168 in O antigen prediction. More attention should be paid to the role of environmental source Escherichia coli in the development and transfer of drug resistance in the hospital environment.

scholarly journals Mechanistic Study of Synergistic Antimicrobial Effects between Poly (3-hydroxybutyrate) Oligomer and Polyethylene Glycol

2020 ◽  
Author(s):  
Ziheng Zhang ◽  
Jun Li ◽  
Linlin Ma ◽  
Xingxing Yang ◽  
Bin Fei ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Antimicrobial Agents ◽  
Antimicrobial Effect ◽  
Mechanistic Study ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Drug Resistant Bacteria

We reported previously that poly (3-hydroxybutyrate) (PHB) oligomer is an effective antimicrobial agent against gram-positive bacteria, gram-negative bacteria, fungi and multi-drug resistant bacteria. In this work, it was further found that polyethylene glycol (PEG) can promote the antimicrobial effect of PHB oligomer synergistically. Three hypothetic mechanisms were proposed, that is, generation of new antimicrobial components, degradation of PHB macromolecules and dissolution/dispersion of PHB oligomer by PEG. With a series of systematic experiments and characterizations of HPLC-MS, it was deducted that dissolution/dispersion of PHB oligomer dominated the synergistic antimicrobial effect between PHB oligomer and PEG. This work demonstrates a way for promoting antimicrobial effect of PHB oligomer and other antimicrobial agents through improving hydrophilicity.

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