The Role of Antimicrobial Peptides in Preventing Multidrug-Resistant Bacterial Infections and Biofilm Formation

Liver transplantation (LT) is a life-saving strategy for patients with end-stage liver disease, hepatocellular carcinoma and acute liver failure. LT success can be hampered by several short-term and long-term complications. Among them, bacterial infections, especially due to multidrug-resistant germs, are particularly frequent with a prevalence between 19 and 33% in the first 100 days after transplantation. In the last decades, a number of studies have highlighted how gut microbiota (GM) is involved in several essential functions to ensure the intestinal homeostasis, becoming one of the most important virtual metabolic organs. GM works through different axes with other organs, and the gut-liver axis is among the most relevant and investigated ones. Any alteration or disruption of GM is defined as dysbiosis. Peculiar phenotypes of GM dysbiosis have been associated to several liver conditions and complications, such as chronic hepatitis, fatty liver disease, cirrhosis and hepatocellular carcinoma. Moreover, there is growing evidence of the crucial role of GM in shaping the immune response, both locally and systemically, against pathogens. This paves the way to the manipulation of GM as a therapeutic instrument to modulate the infectious risk and outcome. In this minireview we provide an overview of the current understanding on the interplay between gut microbiota and the immune system in liver transplant recipients and the role of the former in infections.

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Antimicrobial and Antibiofilm Peptides

Biomolecules ◽

10.3390/biom10040652 ◽

2020 ◽

Vol 10 (4) ◽

pp. 652 ◽

Cited By ~ 12

Author(s):

Angela Di Somma ◽

Antonio Moretta ◽

Carolina Canè ◽

Arianna Cirillo ◽

Angela Duilio

Keyword(s):

Antimicrobial Peptides ◽

Biofilm Formation ◽

Bacterial Resistance ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Antibiofilm Activity ◽

Chronic Infections ◽

Planktonic Bacteria ◽

Hostile Environments

The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to trigger resistance. Besides their activity against planktonic bacteria, many antimicrobial peptides also show antibiofilm activity. Biofilms are ubiquitous in nature, having the ability to adhere to virtually any surface, either biotic or abiotic, including medical devices, causing chronic infections that are difficult to eradicate. The biofilm matrix protects bacteria from hostile environments, thus contributing to the bacterial resistance to antimicrobial agents. Biofilms are very difficult to treat, with options restricted to the use of large doses of antibiotics or the removal of the infected device. Antimicrobial peptides could represent good candidates to develop new antibiofilm drugs as they can act at different stages of biofilm formation, on disparate molecular targets and with various mechanisms of action. These include inhibition of biofilm formation and adhesion, downregulation of quorum sensing factors, and disruption of the pre-formed biofilm. This review focuses on the proprieties of antimicrobial and antibiofilm peptides, with a particular emphasis on their mechanism of action, reporting several examples of peptides that over time have been shown to have activity against biofilm.

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Role of Old Antibiotics in Multidrug Resistant Bacterial Infections

Current Drug Targets ◽

10.2174/138945009789108846 ◽

2009 ◽

Vol 10 (9) ◽

pp. 895-905 ◽

Cited By ~ 50

Author(s):

R. Maviglia ◽

R. Nestorini ◽

M. Pennisi

Keyword(s):

Bacterial Infections ◽

Multidrug Resistant

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Decreased expression of femXAB genes and fnbp mediated biofilm pathways in OS-MRSA clinical isolates

Scientific Reports ◽

10.1038/s41598-019-52557-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Umarani Brahma ◽

Paresh Sharma ◽

Shweta Murthy ◽

Savitri Sharma ◽

Shalini Chakraborty ◽

...

Keyword(s):

Antibiotic Susceptibility ◽

Biofilm Formation ◽

Multidrug Resistant ◽

Agglutination Test ◽

Clinical Isolates ◽

Ocular Infections ◽

Biofilm Production ◽

Fibronectin Binding ◽

Sequence Types

Abstract Methicillin-Resistant Staphylococcus aureus (MRSA) is a significant threat to human health. Additionally, biofilm forming bacteria becomes more tolerant to antibiotics and act as bacterial reservoir leading to chronic infection. In this study, we characterised the antibiotic susceptibility, biofilm production and sequence types (ST) of 74 randomly selected clinical isolates of S. aureus causing ocular infections. Antibiotic susceptibility revealed 74% of the isolates as resistant against one or two antibiotics, followed by 16% multidrug-resistant isolates (MDR), and 10% sensitive. The isolates were characterized as MRSA (n = 15), Methicillin-sensitive S. aureus (MSSA, n = 48) and oxacillin susceptible mecA positive S. aureus (OS-MRSA, n = 11) based on oxacillin susceptibility, mecA gene PCR and PBP2a agglutination test. All OS-MRSA would have been misclassified as MSSA on the basis of susceptibility test. Therefore, both phenotypic and genotypic tests should be included to prevent strain misrepresentation. In addition, in-depth studies for understanding the emerging OS-MRSA phenotype is required. The role of fem XAB gene family has been earlier reported in OS-MRSA phenotype. Sequence analysis of the fem XAB genes revealed mutations in fem × (K3R, H11N, N18H and I51V) and fem B (L410F) genes. The fem XAB genes were also found down-regulated in OS-MRSA isolates in comparison to MRSA. In OS-MRSA isolates, biofilm formation is regulated by fibronectin binding proteins A & B. Molecular typing of the isolates revealed genetic diversity. All the isolates produced biofilm, however, MRSA isolates with strong biofilm phenotype represent a worrisome situation and may even result in treatment failure.

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Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02391-16 ◽

2017 ◽

Vol 61 (4) ◽

Cited By ~ 11

Author(s):

Pooja Manchandani ◽

Jian Zhou ◽

Jessica T. Babic ◽

Kimberly R. Ledesma ◽

Luan D. Truong ◽

...

Keyword(s):

Bacterial Infections ◽

Drug Exposure ◽

Polymyxin B ◽

Multidrug Resistant ◽

Renal Tissue ◽

Sprague Dawley ◽

Electron Microscopic ◽

Drug Concentrations ◽

The Impact

ABSTRACT Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity.

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An Update on Antimicrobial Peptides (AMPs) and Their Delivery Strategies for Wound Infections

Pharmaceutics ◽

10.3390/pharmaceutics12090840 ◽

2020 ◽

Vol 12 (9) ◽

pp. 840 ◽

Cited By ~ 3

Author(s):

Viorica Patrulea ◽

Gerrit Borchard ◽

Olivier Jordan

Keyword(s):

Antimicrobial Peptides ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

New Technologies ◽

Multidrug Resistant ◽

Inorganic Nanoparticles ◽

Wound Dressings ◽

Wound Infections ◽

Clinical Phase ◽

Delivery Strategies

Bacterial infections occur when wound healing fails to reach the final stage of healing, which is usually hindered by the presence of different pathogens. Different topical antimicrobial agents are used to inhibit bacterial growth due to antibiotic failure in reaching the infected site, which is accompanied very often by increased drug resistance and other side effects. In this review, we focus on antimicrobial peptides (AMPs), especially those with a high potential of efficacy against multidrug-resistant and biofilm-forming bacteria and fungi present in wound infections. Currently, different AMPs undergo preclinical and clinical phase to combat infection-related diseases. AMP dendrimers (AMPDs) have been mentioned as potent microbial agents. Various AMP delivery strategies that are used to combat infection and modulate the healing rate—such as polymers, scaffolds, films and wound dressings, and organic and inorganic nanoparticles—have been discussed as well. New technologies such as Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein (CRISPR-Cas) are taken into consideration as potential future tools for AMP delivery in skin therapy.

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Antimicrobial Peptides: A Potent Alternative to Antibiotics

Antibiotics ◽

10.3390/antibiotics10091095 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1095

Author(s):

Mariam Rima ◽

Mohamad Rima ◽

Ziad Fajloun ◽

Jean-Marc Sabatier ◽

Burkhard Bechinger ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Synergistic Activity ◽

Therapeutic Applications ◽

Multidrug Resistant Pathogens ◽

Near Future

Antimicrobial peptides constitute one of the most promising alternatives to antibiotics since they could be used to treat bacterial infections, especially those caused by multidrug-resistant pathogens. Many antimicrobial peptides, with various activity spectra and mechanisms of actions, have been described. This review focuses on their use against ESKAPE bacteria, especially in biofilm treatments, their synergistic activity, and their application as prophylactic agents. Limitations and challenges restricting therapeutic applications are highlighted, and solutions for each challenge are evaluated to analyze whether antimicrobial peptides could replace antibiotics in the near future.

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AMPing up the search: An in silico approach to identifying Antimicrobial Peptides (AMPs) with potential anti-biofilm activity

10.1101/2021.08.16.456477 ◽

2021 ◽

Author(s):

Shreeya Mhade ◽

Stutee Panse ◽

Gandhar Tendulkar ◽

Rohit Awate ◽

Snehal Kadam ◽

...

Keyword(s):

Antimicrobial Peptides ◽

In Silico ◽

Biofilm Formation ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

C Protein ◽

Pilus Biogenesis ◽

Natural And Synthetic

AbstractAntibiotic resistance is a public health threat, and the rise of multidrug-resistant bacteria, including those that form protective biofilms, further compounds this challenge. Antimicrobial peptides (AMPs) have been recognized for their anti-infective properties, including their ability to target processes important for biofilm formation. However, given the vast array of natural and synthetic AMPs, determining potential candidates for anti-biofilm testing is a significant challenge. In this study, we present an in silico approach, based on open-source tools, to identify AMPs with potential anti-biofilm activity. This approach is developed using the sortase-pilin machinery, important for adhesion and biofilm formation, of the multidrug-resistant, biofilm-forming pathogen C. striatum as the target. Using homology modeling, we modeled the structure of the C. striatum sortase C protein, resembling the semi-open lid conformation adopted during pilus biogenesis. Next, we developed a structural library of 5544 natural and synthetic AMPs from sequences in the DRAMP database. From this library, AMPs with known anti-Gram positive activity were filtered, and 100 select AMPs were evaluated for their ability to interact with the sortase C protein using in-silico molecular docking. Based on interacting residues and docking scores, we built a preference scale to categorize candidate AMPs in order of priority for future in vitro and in vivo biofilm studies. The considerations and challenges of our approach, and the resources developed, which includes a search-enabled repository of predicted AMP structures and protein-peptide interaction models relevant to biofilm studies (B-AMP), can be leveraged for similar investigations across other biofilm targets and biofilm-forming pathogens.

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The Effects of β-Lactam Antibiotics on Surface Modifications of Multidrug-Resistant Escherichia coli: A Multiscale Approach

Microscopy and Microanalysis ◽

10.1017/s1431927618015696 ◽

2019 ◽

Vol 25 (1) ◽

pp. 135-150 ◽

Cited By ~ 7

Author(s):

Samuel C. Uzoechi ◽

Nehal I. Abu-Lail

Keyword(s):

Escherichia Coli ◽

Biofilm Formation ◽

Bacterial Infections ◽

Treatment Strategies ◽

Multidrug Resistant ◽

Multiscale Approach ◽

Bacterial Cells ◽

Adhesion Forces ◽

E Coli ◽

Resistant Strains

AbstractPossible multidrug-resistant (MDR) mechanisms of four resistant strains of Escherichia coli to a model β-lactam, ampicillin, were investigated using contact angle measurements of wettability, crystal violet assays of permeability, biofilm formation, fluorescence imaging, and nanoscale analyses of dimensions, adherence, and roughness. Upon exposure to ampicillin, one of the resistant strains, E. coli A5, changed its phenotype from elliptical to spherical, maintained its roughness and biofilm formation abilities, decreased its length and surface area, maintained its cell wall integrity, increased its hydrophobicity, and decreased its nanoscale adhesion to a model surface of silicon nitride. Such modifications are suggested to allow these cells to conserve energy during metabolic dormancy. In comparison, resistant strains E. coli D4, A9, and H5 elongated their cells, increased their roughness, increased their nanoscale adhesion forces, became more hydrophilic, and increased their biofilm formation upon exposure to ampicillin. These results suggest that these strains resisted ampicillin through biofilm formation that possibly introduces diffusion limitations to antibiotics. Investigations of how MDR bacterial cells modify their surfaces in response to antibiotics can guide research efforts aimed at designing more effective antibiotics and new treatment strategies for MDR bacterial infections.

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