scholarly journals Thrombin-Derived Peptides Potentiate the Activity of Gram-Positive-Specific Antibiotics against Gram-Negative Bacteria

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1954
Author(s):  
Charlotte M. J. Wesseling ◽  
Thomas M. Wood ◽  
Kristine Bertheussen ◽  
Samantha Lok ◽  
Nathaniel I. Martin
Keyword(s):  
Antibiotic Resistance ◽  
Outer Membrane ◽  
Therapeutic Range ◽  
Structural Features ◽  
Gram Negative Bacteria ◽  
Binding Properties ◽  
Gram Positive ◽  
Gram Negative ◽  
Recent Attention ◽  
Lps Binding

The continued rise of antibiotic resistance threatens to undermine the utility of the world’s current antibiotic arsenal. This problem is particularly troubling when it comes to Gram-negative pathogens for which there are inherently fewer antibiotics available. To address this challenge, recent attention has been focused on finding compounds capable of disrupting the Gram-negative outer membrane as a means of potentiating otherwise Gram-positive-specific antibiotics. In this regard, agents capable of binding to the lipopolysaccharide (LPS) present in the Gram-negative outer membrane are of particular interest as synergists. Recently, thrombin-derived C-terminal peptides (TCPs) were reported to exhibit unique LPS-binding properties. We here describe investigations establishing the capacity of TCPs to act as synergists with the antibiotics erythromycin, rifampicin, novobiocin, and vancomycin against multiple Gram-negative strains including polymyxin-resistant clinical isolates. We further assessed the structural features most important for the observed synergy and characterized the outer membrane permeabilizing activity of the most potent synergists. Our investigations highlight the potential for such peptides in expanding the therapeutic range of antibiotics typically only used to treat Gram-positive infections.

scholarly journals Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Craig R. MacNair ◽  
Eric D. Brown
Keyword(s):  
Antibiotic Resistance ◽  
Outer Membrane ◽  
Biofilm Formation ◽  
Antibiotic Use ◽  
Membrane Disruption ◽  
Permeability Barrier ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Outer Membrane Permeability

ABSTRACT Disruption of the outer membrane (OM) barrier allows for the entry of otherwise inactive antimicrobials into Gram-negative pathogens. Numerous efforts to implement this approach have identified a large number of OM perturbants that sensitize Gram-negative bacteria to many clinically available Gram-positive active antibiotics. However, there is a dearth of investigation into the strengths and limitations of this therapeutic strategy, with an overwhelming focus on characterization of individual potentiator molecules. Herein, we look to explore the utility of exploiting OM perturbation to sensitize Gram-negative pathogens to otherwise inactive antimicrobials. We identify the ability of OM disruption to change the rules of Gram-negative entry, overcome preexisting and spontaneous resistance, and impact biofilm formation. Disruption of the OM expands the threshold of hydrophobicity compatible with Gram-negative activity to include hydrophobic molecules. We demonstrate that while resistance to Gram-positive active antibiotics is surprisingly common in Gram-negative pathogens, OM perturbation overcomes many antibiotic inactivation determinants. Further, we find that OM perturbation reduces the rate of spontaneous resistance to rifampicin and impairs biofilm formation. Together, these data suggest that OM disruption overcomes many of the traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development. IMPORTANCE The spread of antibiotic resistance is an urgent threat to global health that necessitates new therapeutics. Treatments for Gram-negative pathogens are particularly challenging to identify due to the robust outer membrane permeability barrier in these organisms. Recent discovery efforts have attempted to overcome this hurdle by disrupting the outer membrane using chemical perturbants and have yielded several new peptides and small molecules that allow the entry of otherwise inactive antimicrobials. However, a comprehensive investigation into the strengths and limitations of outer membrane perturbants as antibiotic partners is currently lacking. Herein, we interrogate the interaction between outer membrane perturbation and several common impediments to effective antibiotic use. Interestingly, we discover that outer membrane disruption is able to overcome intrinsic, spontaneous, and acquired antibiotic resistance in Gram-negative bacteria, meriting increased attention toward this approach.

scholarly journals Rationalizing generation of broad spectrum antibiotics with the addition of a positive charge

2021 ◽  
Author(s):  
nandan haloi ◽  
Archit Kumar Vasan ◽  
Emily Jane Geddes ◽  
Arjun Prasanna ◽  
Po-Chao Wen ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Outer Membrane ◽  
Broad Spectrum ◽  
Positive Charge ◽  
Low Permeability ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Broad Spectrum Antibiotics

Antibiotic resistance of Gram-negative bacteria is largely attributed to the low permeability of their outer membrane (OM). Recently, we disclosed the eNTRy rules, a key lesson of which is that...

scholarly journals Pattern of antibiotic resistance of various strains of bacteria causing acute tonsillitis

2021 ◽  
Vol 7 (6) ◽  
pp. 994
Author(s):  
N. Jyothsna ◽  
A. Ramya ◽  
K. Abhilash ◽  
Bathsa Liza Johnson
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Growth ◽  
Bacterial Strain ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Acute Tonsillitis ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Antibiotic Drugs ◽  
Significant Difference

<p class="abstract"><strong>Background:</strong> Our study was done to determine the pattern of antibiotic resistance of various strains of bacteria causing acute tonsillitis.</p><p class="abstract"><strong>Methods:</strong> the study was a randomized cross sectional study. Patients matching the inclusion criteria were included. Duration of study was 6 months.</p><p class="abstract"><strong>Results:</strong> Out of 120 cases, 46 cases showed no bacterial growth (NBG) and 74 cases showed bacterial growth. 42 cases were gram-negative bacterial strain and 32 cases were positive bacterial strain out of 72 bacterial grown cases. A list of 25 antibiotic drugs in gram-negative and 31 drugs in gram-positive strain, their sensitivity and resistance were taken and noted. Among gram-negative bacteria imipenem (71.4%) showed highest sensitivity. Highest antibiotic resistance was seen in ampicillin (85.71%). Least sensitivity is observed in clindamycin, amoxicillin+clavulanic acid with 2.38%. Among gram-positive bacteria, highest sensitivity was noted in cefotaxime (75%). Highest antibiotic resistance was seen in cotrimoxazole (46.8%). Least sensitivity is observed in netilmicin, sulbactam with 3.12%.</p><p class="abstract"><strong>Conclusions:</strong> The number of drugs resistant to the gram-positive bacteria are lesser than number of drugs sensitive, which showed significant difference (p&lt;0.05). Significant difference of antibiotic drugs was not found in gram-negative bacteria. Our study findings helped in appropriate and guarded use of the antibiotic drugs in acute tonsillitis, minimizing the exposure of individuals to antibiotic resistance by choosing an appropriate sensitive drug, therefore improving the quality of therapy.</p>

scholarly journals The essential inner membrane protein YejM is a metalloenzyme

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Uma Gabale ◽  
Perla Arianna Peña Palomino ◽  
HyunAh Kim ◽  
Wenya Chen ◽  
Susanne Ressl
Keyword(s):  
Antibiotic Resistance ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Critical Role ◽  
Membrane Properties ◽  
Gram Negative Bacteria ◽  
Inner Membrane ◽  
Gram Negative ◽  
Periplasmic Domain ◽  
Inner Membrane Protein

Abstract Recent recurrent outbreaks of Gram-negative bacteria show the critical need to target essential bacterial mechanisms to fight the increase of antibiotic resistance. Pathogenic Gram-negative bacteria have developed several strategies to protect themselves against the host immune response and antibiotics. One such strategy is to remodel the outer membrane where several genes are involved. yejM was discovered as an essential gene in E. coli and S. typhimurium that plays a critical role in their virulence by changing the outer membrane permeability. How the inner membrane protein YejM with its periplasmic domain changes membrane properties remains unknown. Despite overwhelming structural similarity between the periplasmic domains of two YejM homologues with hydrolases like arylsulfatases, no enzymatic activity has been previously reported for YejM. Our studies reveal an intact active site with bound metal ions in the structure of YejM periplasmic domain. Furthermore, we show that YejM has a phosphatase activity that is dependent on the presence of magnesium ions and is linked to its function of regulating outer membrane properties. Understanding the molecular mechanism by which YejM is involved in outer membrane remodeling will help to identify a new drug target in the fight against the increased antibiotic resistance.

Monitoring of the leading causative agents of osteomyelitis and their antibiotic resistance

2020 ◽  
Vol 65 (9) ◽  
pp. 562-566
Author(s):  
I. V. Shipitsyna ◽  
E. V. Osipova ◽  
O. A. Astashova ◽  
D. S. Leonchuk
Keyword(s):  
Antibiotic Resistance ◽  
Species Composition ◽  
Antibiotic Sensitivity ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Methicillin Resistant ◽  
Causative Agents ◽  
Resistant Strains ◽  
Bacterial Associations

The annual monitoring of the species composition of the causative agents of osteomyelitis, the identification of antibiotic-resistant strains, the study of the species composition of associations of microorganisms, their adhesive activity will prevent the spread of infection. Analyze the spectrum of the leading causative agents of osteomyelitis, their antibiotic sensitivity, and also the adhesive activity of the identified bacterial associations. A microbiological analysis of 2197 smears of adult patients with various etiological forms of osteomyelitis who were treated in the departments of the purulent center of the FSBI «NMRCTO» of the RF Ministry of Health in 2019. The spectrum of pathogenic microflora, sensitivity to standard antibacterial drugs used in the clinic was studied. The biofilm-forming ability of associations of microorganisms was investigated. According to the conducted microbiological monitoring for 2019, the microflora spectrum for osteomyelitis is diverse, the main pathogens are S. aureus, S. epidermidis, P. aeruginosa, K. pneumoniae, Enterococcus sp. A high percentage of isolation of microbial associations was noted, most often mix cultures of gram-positive and gram-negative bacteria. Bacterial associations: S. aureus + P. aeruginosa, S. aureus + S. marcescens, S. aureus + A. baumannii, S. epidermidis + E. cloacae - actively formed a biofilm on the surface of polystyrene plates, and the adhesive potential depended on interstrain relations in the composition of the formed biofilm. Among Gram-negative microflora, multiresistant strains prevail, among Gram-positive microflora - a high percentage of methicillin-resistant Staphylococci. When analyzing the antibiotic sensitivity of the isolated microorganisms, a high percentage of resistant strains is noted. So, with respect to enterobacteria, β-lactam antibiotics, drugs from the group of aminoglycosides, turned out to be ineffective. Among non-fermenting gram-negative bacteria, A. baumannii strains had multiple antimicrobial resistance. Among gram-positive microorganisms, a high percentage of isolation of methicillin-resistant staphylococci was noted. The specificity of the course of the disease and measures aimed at eliminating the pathogen depend on the species composition in the focus of infection. The study of the etiological structure of osteomyelitis, the monitoring of the antibiotic resistance of pathogens and their persistent potential, makes it possible to adopt sound tactics of conservative and surgical treatment.

scholarly journals Physicochemical Properties That Enhance Discriminative Antibacterial Activity of Short Dermaseptin Derivatives

2006 ◽  
Vol 50 (8) ◽  
pp. 2666-2672 ◽  
Author(s):  
Shahar Rotem ◽  
Inna Radzishevsky ◽  
Amram Mor
Keyword(s):  
Antimicrobial Peptides ◽  
Physicochemical Properties ◽  
Culture Media ◽  
Gram Negative Bacteria ◽  
Terminal Sequence ◽  
Binding Properties ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Cytoplasmic Membranes

ABSTRACT Antimicrobial peptides are widely believed to exert their effects by nonspecific mechanisms. We assessed the extent to which physicochemical properties can be exploited to promote discriminative activity by manipulating the N-terminal sequence of the 13-mer dermaseptin derivative K4-S4(1-13) (P). Inhibitory activity determined in culture media against 16 strains of bacteria showed that when its hydrophobicity and charge were changed, P became predominantly active against either gram-positive or gram-negative bacteria. Thus, conjugation of various aminoacyl-lysin moieties (e.g., aminohexyl-K-P) led to inactivity against gram-positive bacteria (MIC50 > 50 μM) but potent activity against gram-negative bacteria (MIC50, 6.2 μM). Conversely, conjugation of equivalent acyls to the substituted analog M4-S4(1-13) (e.g., hexyl-M4-P) led to inactivity against gram-negative bacteria (MIC50 > 50 μM) but potent activity against gram-positive bacteria (MIC50, 3.1 μM). Surface plasmon resonance experiments, used to investigate peptides' binding properties to lipopolysaccharide-containing idealized phospholipid membranes, suggest that although the acylated derivatives have increased lipophilic properties with parallel antibacterial behavior, hydrophobic derivatives are prevented from reaching the cytoplasmic membranes of gram-negative bacteria. Moreover, unlike modifications that enhanced the activity against gram-positive bacteria, which also enhanced hemolysis, we found that modifications that enhanced activity against gram-negative bacteria generally reduced hemolysis. Thus, compared with the clinically tested peptides MSI-78 and IB-367, the dermaseptin derivative aminohexyl-K-P performed similarly in terms of potency and bactericidal kinetics but was significantly more selective in terms of discrimination between bacteria and human erythrocytes. Overall, the data suggest that similar strategies maybe useful to derive potent and safe compounds from known antimicrobial peptides.

scholarly journals An Essential Membrane Protein Modulates the Proteolysis of LpxC to Control Lipopolysaccharide Synthesis in Escherichia coli

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Elayne M. Fivenson ◽  
Thomas G. Bernhardt
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Outer Membrane ◽  
Unknown Function ◽  
Barrier Function ◽  
Major Determinant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Essential Protein

ABSTRACT Gram-negative bacteria are surrounded by a complex cell envelope that includes two membranes. The outer membrane prevents many drugs from entering these cells and is thus a major determinant of their intrinsic antibiotic resistance. This barrier function is imparted by the asymmetric architecture of the membrane with lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner leaflet. The LPS and phospholipid synthesis pathways share an intermediate. Proper membrane biogenesis therefore requires that the flux through each pathway be balanced. In Escherichia coli, a major control point in establishing this balance is the committed step of LPS synthesis mediated by LpxC. Levels of this enzyme are controlled through its degradation by the inner membrane protease FtsH and its presumed adapter protein LapB (YciM). How turnover of LpxC is controlled has remained unclear for many years. Here, we demonstrate that the essential protein of unknown function YejM (PbgA) participates in this regulatory pathway. Suppressors of YejM essentiality were identified in lpxC and lapB, and LpxC overproduction was shown to be sufficient to allow survival of ΔyejM mutants. Furthermore, the stability of LpxC was shown to be reduced in cells lacking YejM, and genetic and physical interactions between LapB and YejM were detected. Taken together, our results are consistent with a model in which YejM directly modulates LpxC turnover by FtsH-LapB to regulate LPS synthesis and maintain membrane homeostasis. IMPORTANCE The outer membrane is a major determinant of the intrinsic antibiotic resistance of Gram-negative bacteria. It is composed of both lipopolysaccharide (LPS) and phospholipid, and the synthesis of these lipid species must be balanced for the membrane to maintain its barrier function in blocking drug entry. In this study, we identified an essential protein of unknown function as a key new factor in modulating LPS synthesis in the model bacterium Escherichia coli. Our results provide novel insight into how this organism and most likely other Gram-negative bacteria maintain membrane homeostasis and their intrinsic resistance to antibiotics.

scholarly journals The Antibacterial Activities of NiO Nanoparticles Against Some Gram-Positive and Gram-Negative Bacterial Strains

2019 ◽  
Vol 4 (2) ◽  
pp. 69-74
Author(s):  
Ghazaleh Ilbeigi ◽  
Ashraf Kariminik ◽  
Mohammad Hasan Moshafi
Keyword(s):  
Antibiotic Resistance ◽  
Antibacterial Properties ◽  
Diffusion Method ◽  
Resistance Pattern ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Nio Nanoparticles ◽  
Bacterial Strains ◽  
Gram Positive ◽  
Gram Negative

Introduction: Given the increasing rate of antibiotic resistance among bacterial strains, many researchers have been working to produce new and efficient and inexpensive antibacterial agents. It has been reported that some nanoparticles may be used as novel antimicrobial agents.Here, we evaluated antibacterial properties of nickel oxide (NiO) nanoparticles. Methods: NiO nanoparticles were synthesized using microwave method. In order to control the quality and morphology of nanoparticles, XRD (X-ray diffraction) and SEM (scanning electronmicroscope) were utilized. The antibacterial properties of the nanoparticles were assessed against eight common bacterial strains using agar well diffusion assay. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were measured. Antibiotic resistance pattern of the bacteria to nine antibiotics was obtained by Kirby-Bauer disk diffusion method. Results: The crystalline size and diameter (Dc) of NiO nanoparticles were obtained 40-60 nm. The nanoparticles were found to inhibit the growth of both gram-positive and gram-negative bacteria with higher activity against gram-positive organisms. Among bacterial strains, maximum sensitivity was observed in Staphylococcus epidermidis with MIC and MBC of 0.39 and 0.78 mg/mL, respectively. The bacteria had high resistance to cefazolin, erythromycin, rifampicin,ampicillin, penicillin and streptomycin.Conclusion: NiO nanoparticles exhibited remarkable antibacterial properties against gram positive and gram-negative bacteria and can be a new treatment for human pathogenic and antibiotic-resistant bacteria.

scholarly journals MICROBIAL DIVERSITY AND ANTIBIOTIC RESISTANCE OF BACTERIA ON WASHROOM FOMITES IN A PUBLIC UNIVERSITY

2020 ◽  
Vol 5 (1) ◽  
pp. 1 ◽  
Author(s):  
Reuben Essel Arhin ◽  
Henry Kwadwo Hackman ◽  
Barry Kojo Whyte ◽  
Alhassan Sa-eed
Keyword(s):  
Antibiotic Resistance ◽  
Healthcare Setting ◽  
Public University ◽  
Healthy Population ◽  
Gram Negative Bacteria ◽  
Unique Contribution ◽  
Gram Positive ◽  
Gram Negative ◽  
Healthcare Settings ◽  
Skin Flora

Purpose: To determine the diversity and distribution of bacteria contaminants on washroom fomites in a public university and their resistance to common antibiotics.Methodology: A sanitation audit was conducted on 21 selected washrooms on seven different blocks in a university. Swabs were collected from 68 washroom fomites for bacterial isolation and biochemical identification. Antimicrobial susceptibility testing was performed for 22 Gram positive and 41 Gram negative bacteria species.Findings: Of 21 washrooms none had toiletries, 71% did not have flowing water and 90% were in the category of generally unclean. Of 169 bacteria isolated Staphylococcus aureus and Escherichia coli were the predominant species. Of 68 fomites all had bacterial contaminants with 83.8% having 2 to 3 co-occurring species. Gram positive bacteria isolated were resistant to augmentin (100%), meropenem (94%), penicillin (91%), cefuroxime (86%), vancomycin (86%), erythromycin (67%), cloxacillin (64%), tetracyclin (64%), ciprofloxacin (59%), cotrimoxazole (59%), ampicillin (50%) and gentamicin (36%). Gram negative bacteria isolated were resistant to meropenem (97%), ceftriaxone (95%), ampicillin (93%), cefuroxime (91%), cefotaxime (84%), vancomycin (82%), tetracyclin (80%), cotrimoxazole (78%), chloramphenicol (50%), ciprofloxacin (71%), amikacin (40%) and gentamicin (24%). Unique contribution to theory, practice and policy: Previous studies on bacteria on fomites in Ghana have focused on healthcare settings. This study focused on a university campus which is a non-healthcare setting with a high human presence and pressure on existing washroom facilities leading to contamination. The diversity of bacteria on the fomites are representative of clinically significant antibiotic resistant human enteric and skin flora carried by a seemingly healthy population and provide an indication of the potential antibiotic resistance burden in the user community.

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