scholarly journals NMR Study of the Secondary Structure and Biopharmaceutical Formulation of an Active Branched Antimicrobial Peptide

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4290 ◽  
Author(s):  
Francesca Castiglia ◽  
Fabrizia Zevolini ◽  
Giulia Riolo ◽  
Jlenia Brunetti ◽  
Alessandra De Lazzari ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Antimicrobial Peptide ◽  
Process Development ◽  
Pharmacokinetic Profile ◽  
Point Of View ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Acinetobacter Baumanii ◽  
Gram Negative ◽  
Nmr Study

The synthetic antimicrobial peptide SET-M33 is being developed as a possible new antibacterial candidate for the treatment of multi-drug resistant bacteria. SET-M33 is a branched peptide featuring higher resistance and bioavailability than its linear analogues. SET-M33 shows antimicrobial activity against different species of multi-resistant Gram-negative bacteria, including clinically isolated strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii and Escherichia coli. The secondary structure of this 40 amino acid peptide was investigated by NMR to fully characterize the product in the framework of preclinical studies. The possible presence of helixes or β-sheets in the structure had to be explored to predict the behavior of the branched peptide in solution, with a view to designing a formulation for parenteral administration. Since the final formulation of SET-M33 will be strictly defined in terms of counter-ions and additives, we also report the studies on a new salt form, SET-M33 chloride, that retains its activity against Gram-negative bacteria and gains in solubility, with a possible improvement in the pharmacokinetic profile. The opportunity of using a chloride counter-ion is very convenient from a process development point of view and did not increase the toxicity of the antimicrobial drug.

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 Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2987 ◽  
Author(s):  
Cornelius Domhan ◽  
Philipp Uhl ◽  
Christian Kleist ◽  
Stefan Zimmermann ◽  
Florian Umstätter ◽  
...  
Keyword(s):  
Amino Acids ◽  
Antimicrobial Activity ◽  
Antimicrobial Peptide ◽  
The Body ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Strong Antimicrobial Activity

Infections caused by multidrug-resistant bacteria are a global emerging problem. New antibiotics that rely on innovative modes of action are urgently needed. Ranalexin is a potent antimicrobial peptide (AMP) produced in the skin of the American bullfrog Rana catesbeiana. Despite strong antimicrobial activity against Gram-positive bacteria, ranalexin shows disadvantages such as poor pharmacokinetics. To tackle these problems, a ranalexin derivative consisting exclusively of d-amino acids (named danalexin) was synthesized and compared to the original ranalexin for its antimicrobial potential and its biodistribution properties in a rat model. Danalexin showed improved biodistribution with an extended retention in the organisms of Wistar rats when compared to ranalexin. While ranalexin is rapidly cleared from the body, danalexin is retained primarily in the kidneys. Remarkably, both peptides showed strong antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria of the genus Acinetobacter with minimum inhibitory concentrations (MICs) between 4 and 16 mg/L (1.9–7.6 µM). Moreover, both peptides showed lower antimicrobial activities with MICs ≥32 mg/L (≥15.2 µM) against further Gram-negative bacteria. The preservation of antimicrobial activity proves that the configuration of the amino acids does not affect the anticipated mechanism of action, namely pore formation.

scholarly journals Interaction of Antimicrobial Peptide Temporin L with Lipopolysaccharide In Vitro and in Experimental Rat Models of Septic Shock Caused by Gram-Negative Bacteria

2006 ◽  
Vol 50 (7) ◽  
pp. 2478-2486 ◽  
Author(s):  
Andrea Giacometti ◽  
Oscar Cirioni ◽  
Roberto Ghiselli ◽  
Federico Mocchegiani ◽  
Fiorenza Orlando ◽  
...  
Keyword(s):  
Septic Shock ◽  
Antimicrobial Peptide ◽  
Gram Negative Bacteria ◽  
Amphibian Skin ◽  
Necrosis Factor Alpha ◽  
Gram Negative ◽  
Rat Models ◽  
E Coli ◽  
Tnf Α

ABSTRACT Sepsis remains a major cause of morbidity and mortality in hospitalized patients, despite intense efforts to improve survival. The primary lead for septic shock results from activation of host effector cells by endotoxin, the lipopolysaccharide (LPS) associated with cell membranes of gram-negative bacteria. For these reasons, the quest for compounds with antiendotoxin properties is actively pursued. We investigated the efficacy of the amphibian skin antimicrobial peptide temporin L in binding Escherichia coli LPS in vitro and counteracting its effects in vivo. Temporin L strongly bound to purified E. coli LPS and lipid A in vitro, as proven by fluorescent displacement assay, and readily penetrated into E. coli LPS monolayers. Furthermore, the killing activity of temporin L against E. coli was progressively inhibited by increasing concentrations of LPS added to the medium, further confirming the peptide's affinity for endotoxin. Antimicrobial assays showed that temporin L interacted synergistically with the clinically used β-lactam antibiotics piperacillin and imipenem. Therefore, we characterized the activity of temporin L when combined with imipenem and piperacillin in the prevention of lethality in two rat models of septic shock, measuring bacterial growth in blood and intra-abdominal fluid, endotoxin and tumor necrosis factor alpha (TNF-α) concentrations in plasma, and lethality. With respect to controls and single-drug treatments, the simultaneous administration of temporin L and β-lactams produced the highest antimicrobial activities and the strongest reduction in plasma endotoxin and TNF-α levels, resulting in the highest survival rates.

scholarly journals Improved Derivatives of Bactenecin, a Cyclic Dodecameric Antimicrobial Cationic Peptide

1999 ◽  
Vol 43 (5) ◽  
pp. 1274-1276 ◽  
Author(s):  
Manhong Wu ◽  
Robert E. W. Hancock
Keyword(s):  
Amino Acid ◽  
Antimicrobial Peptide ◽  
Tryptophan Residue ◽  
Gram Negative Bacteria ◽  
Cationic Peptide ◽  
Gram Positive ◽  
Antimicrobial Spectrum ◽  
Gram Negative ◽  
Derivatives Of

ABSTRACT Both linear and cyclic derivatives of the cyclic 12-amino-acid antimicrobial peptide bactenecin were designed based on optimization of amphipathicity and charge location. In general, increasing the number of positive charges at the N and C termini and adding an extra tryptophan residue in the loop not only increased the activities against both gram-positive and gram-negative bacteria but also broadened the antimicrobial spectrum.

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 Interactions of an antimicrobial peptide, magainin 2, with outer and inner membranes of Gram-negative bacteria

1997 ◽  
Vol 1327 (1) ◽  
pp. 119-130 ◽  
Author(s):  
Katsumi Matsuzaki ◽  
Ken-ichi Sugishita ◽  
Mitsunori Harada ◽  
Nobutaka Fujii ◽  
Koichiro Miyajima
Keyword(s):  
Antimicrobial Peptide ◽  
Gram Negative Bacteria ◽  
Gram Negative

Microbiological pattern of prosthetic hip and knee infections: a high-volume, single-centre experience in China

2021 ◽  
Author(s):  
Yali Yu ◽  
Yiyi Kong ◽  
Jing Ye ◽  
Aiguo Wang ◽  
Wenteng Si
Keyword(s):  
Antibiotic Treatment ◽  
Prolonged Treatment ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Musculoskeletal Infection ◽  
Gram Negative ◽  
Content Type ◽  
Empirical Antibiotic Treatment ◽  
Link Type

Introduction. Prosthetic joint infection (PJI) is a serious complication after arthroplasty, which results in high morbidity, prolonged treatment and considerable healthcare expenses in the absence of accurate diagnosis. In China, microbiological data on PJIs are still scarce. Hypothesis/Gap Statement. The incidence of PJI is increasing year by year, and the proportion of drug-resistant bacteria infection is nicreasing, which brings severe challenges to the treatment of infection. Aim. This study aimed to identify the pathogens in PJIs, multi-drug resistance, and evaluate the effect of the treatment regimen in patients with PJI. Methodology. A total of 366 consecutive cases of PJI in the hip or knee joint were admitted at the Orthopedic Surgery Center in Zhengzhou, China from January 2012 to December 2018. Infections were confirmed in accordance with the Infectious Diseases Society of America and the Musculoskeletal Infection Society (MSIS) criteria. Concurrently, patient demographic data, incidence and antibiotic resistance were investigated. Statistical differences were analysed using Fisher’s exact test or chi-square test. Results. Altogether, 318 PJI cases satisfying the inclusion criteria were enrolled in this study, including 148 with hip PJIs and 170 with knee PJIs. The average age of patients with hip PJIs was lesser than that of patients with knee PJIs (56.4 vs. 68.6 years). Meanwhile, coagulase-negative staphylococcus (CNS, n=81, 25.5 %) was the predominant causative pathogen, followed by Staphylococcus aureus (n=67, 21.1 %). Methicillin-resistant Staphylococcus (MRS) was identified in 28.9 % of PJI patients. In addition, fungus accounted for 4.8 % (n=15), non-tuberculosis mycobacterium accounted for 1.6 % (n=5), polymicrobial pathogens accounted for 21.7 % (n=69), and Gram-negative bacteria accounted for 7.9 % (n=25) of the total infections. The results of antibiotic susceptibility testing showed that gentamicin and clindamycin β-lactam antibiotics were poorly susceptible to Gram-positive isolates, but they were sensitive to rifampicin, linezolid and vancomycin. While antibiotics such as amikacin and imipenem were effective against Gram-negative bacteria, there was a high resistance rate of other pathogens to gentamicin, clindamycin and some quinolone antibacterial drugs. Empirical antibiotic treatment should combine vancomycin and cephalosporin, levofloxacin or clindamycin. When the pathogen is confirmed, the treatment should be individualized. Conclusions. The prevalence of culture-negative PJIs is still very high. Gram-positive bacteria are still the main type of pathogens that cause PJIs. Attention should be paid to the high incidence of MRS, such as MRSA and MR-CNS, among PJI patients. Empirical antibiotic treatment should cover Gram-positive isolates, especially Staphylococcus .

scholarly journals “Clicking” an Ionic Liquid to a Potent Antimicrobial Peptide: On the Route towards Improved Stability

2020 ◽  
Vol 21 (17) ◽  
pp. 6174
Author(s):  
Ana Gomes ◽  
Lucinda J. Bessa ◽  
Patrícia Correia ◽  
Iva Fernandes ◽  
Ricardo Ferraz ◽  
...  
Keyword(s):  
Ionic Liquid ◽  
Ionic Liquids ◽  
Klebsiella Pneumoniae ◽  
Antimicrobial Peptide ◽  
Clinical Isolate ◽  
Bioactive Peptides ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Improved Stability

A covalent conjugate between an antibacterial ionic liquid and an antimicrobial peptide was produced via “click” chemistry, and found to retain the parent peptide’s activity against multidrug-resistant clinical isolates of Gram-negative bacteria, and antibiofilm action on a resistant clinical isolate of Klebsiella pneumoniae, while exhibiting much improved stability towards tyrosinase-mediated modifications. This unprecedented communication is a prelude for the promise held by ionic liquids -based approaches as tools to improve the action of bioactive peptides.

scholarly journals A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier

2019 ◽  
Vol 116 (43) ◽  
pp. 21748-21757 ◽  
Author(s):  
Elizabeth M. Hart ◽  
Angela M. Mitchell ◽  
Anna Konovalova ◽  
Marcin Grabowicz ◽  
Jessica Sheng ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Small Molecule ◽  
Cytoplasmic Membrane ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bam Complex ◽  
Induced Aggregation

The development of new antimicrobial drugs is a priority to combat the increasing spread of multidrug-resistant bacteria. This development is especially problematic in gram-negative bacteria due to the outer membrane (OM) permeability barrier and multidrug efflux pumps. Therefore, we screened for compounds that target essential, nonredundant, surface-exposed processes in gram-negative bacteria. We identified a compound, MRL-494, that inhibits assembly of OM proteins (OMPs) by the β-barrel assembly machine (BAM complex). The BAM complex contains one essential surface-exposed protein, BamA. We constructed a bamA mutagenesis library, screened for resistance to MRL-494, and identified the mutation bamAE470K. BamAE470K restores OMP biogenesis in the presence of MRL-494. The mutant protein has both altered conformation and activity, suggesting it could either inhibit MRL-494 binding or allow BamA to function in the presence of MRL-494. By cellular thermal shift assay (CETSA), we determined that MRL-494 stabilizes BamA and BamAE470K from thermally induced aggregation, indicating direct or proximal binding to both BamA and BamAE470K. Thus, it is the altered activity of BamAE470K responsible for resistance to MRL-494. Strikingly, MRL-494 possesses a second mechanism of action that kills gram-positive organisms. In microbes lacking an OM, MRL-494 lethally disrupts the cytoplasmic membrane. We suggest that the compound cannot disrupt the cytoplasmic membrane of gram-negative bacteria because it cannot penetrate the OM. Instead, MRL-494 inhibits OMP biogenesis from outside the OM by targeting BamA. The identification of a small molecule that inhibits OMP biogenesis at the cell surface represents a distinct class of antibacterial agents.

scholarly journals Antibiotic Resistance of Gram-Negative Bacteria from Wild Captured Loggerhead Sea Turtles

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 162 ◽  
Author(s):  
Monica Francesca Blasi ◽  
Luciana Migliore ◽  
Daniela Mattei ◽  
Alice Rotini ◽  
Maria Cristina Thaller ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Sea Turtles ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Marine Animals ◽  
Loggerhead Sea Turtles ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Marine Habitats ◽  
Resistant Strains

Sea turtles have been proposed as health indicators of marine habitats and carriers of antibiotic-resistant bacterial strains, for their longevity and migratory lifestyle. Up to now, a few studies evaluated the antibacterial resistant flora of Mediterranean loggerhead sea turtles (Caretta caretta) and most of them were carried out on stranded or recovered animals. In this study, the isolation and the antibiotic resistance profile of 90 Gram negative bacteria from cloacal swabs of 33 Mediterranean wild captured loggerhead sea turtles are described. Among sea turtles found in their foraging sites, 23 were in good health and 10 needed recovery for different health problems (hereafter named weak). Isolated cloacal bacteria belonged mainly to Enterobacteriaceae (59%), Shewanellaceae (31%) and Vibrionaceae families (5%). Although slight differences in the bacterial composition, healthy and weak sea turtles shared antibiotic-resistant strains. In total, 74 strains were endowed with one or multi resistance (up to five different drugs) phenotypes, mainly towards ampicillin (~70%) or sulfamethoxazole/trimethoprim (more than 30%). Hence, our results confirmed the presence of antibiotic-resistant strains also in healthy marine animals and the role of the loggerhead sea turtles in spreading antibiotic-resistant bacteria.

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