scholarly journals Slow andad hoc: Unravelling the two features characterizing the development of bacterial resistance to membrane active peptides

2019 ◽  
Author(s):  
Ayan Majumder ◽  
Meher K. Prakash
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Serial Passage ◽  
Membrane Composition ◽  
Drug Pressure ◽  
Active Peptides ◽  
Development Of Resistance ◽  
Membrane Adaptation ◽  
Membrane Active Peptides ◽  
Drug Free

AbstractMembrane disrupting drugs such as antimicrobial peptides are being considered as a solution to counter the problem of antibiotic resistance. Although it can be intuitively imagined that bacteria will eventually develop resistance to this class of drugs as well, the concern has largely been ignored. Drawing upon the experimental data from the resistance ofStaphylococcus aureusto antimicrobial peptides, we theoretically model the membrane adaptation under drug pressure. Using our model, we simulate the serial passage experiments with and without the drug pressure, and use the comparisons with experiments to estimate the unknown kinetic parameters. While the development of resistance to enzyme or membrane targeting drugs are both driven by spontaneous mutations, an additional lysylation step required in the latter slows the development of resistance. By quantifying the tradeoff between the gain in fitness under drug pressure and a loss in growth due to membrane modification, our model shows a fast reversal of membrane composition in drug free conditions, re-sensitizing the bacterium to the drugs.

scholarly journals Membrane Active Peptides and Their Biophysical Characterization

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 77 ◽  
Author(s):  
Fatma Gizem Avci ◽  
Berna Sariyar Akbulut ◽  
Elif Ozkirimli
Keyword(s):  
Antimicrobial Peptides ◽  
Single Molecule ◽  
Imaging Techniques ◽  
Membrane Integrity ◽  
Cell Penetrating Peptides ◽  
Single Molecule Level ◽  
Active Peptides ◽  
Cell Penetrating ◽  
Biophysical Techniques ◽  
Membrane Active Peptides

In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. Membrane active peptides are attractive alternatives to currently used pharmaceuticals and the number of antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery in the drug pipeline is increasing. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). Antimicrobial peptides are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus, and fungi. Cell penetrating peptides are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity. Biophysical techniques shed light on peptide–membrane interactions at higher resolution due to the advances in optics, image processing, and computational resources. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Live imaging techniques allow examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provide clues on the peptide–lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC.

scholarly journals The Lactococcal dgkB (yecE) and dxsA Genes for Lipid Metabolism Are Involved in the Resistance to Cell Envelope-Acting Antimicrobials

2021 ◽  
Vol 22 (3) ◽  
pp. 1014
Author(s):  
Aleksandra Tymoszewska ◽  
Tamara Aleksandrzak-Piekarczyk
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Cytoplasmic Membrane ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Membrane Targeting ◽  
Nucleotide Polymorphisms ◽  
Next Generation ◽  
Lipid Ii

The emergence of antibiotic-resistant bacteria led to an urgent need for next-generation antimicrobial agents with novel mechanisms of action. The use of positively charged antimicrobial peptides that target cytoplasmic membrane is an especially promising strategy since essential functions and the conserved structure of the membrane hinder the development of bacterial resistance. Aureocin A53- and enterocin L50-like bacteriocins are highly cationic, membrane-targeting antimicrobial peptides that have potential as next-generation antibiotics. However, the mechanisms of resistance to these bacteriocins and cross-resistance against antibiotics must be examined before application to ensure their safe use. Here, in the model bacterium Lactococcus lactis, we studied the development of resistance to selected aureocin A53- and enterocin L50-like bacteriocins and its correlation with antibiotics. First, to generate spontaneous resistant mutants, L.lactis was exposed to bacteriocin BHT-B. Sequencing of their genomes revealed single nucleotide polymorphisms (SNPs) in the dgkB (yecE) and dxsA genes encoding diacylglycerol kinase and 1-deoxy-D-xylulose 5-phosphate synthase, respectively. Then, selected mutants underwent susceptibility tests with a wide array of bacteriocins and antibiotics. The highest alterations in the sensitivity of studied mutants were seen in the presence of cytoplasmic membrane targeting bacteriocins (K411, Ent7, EntL50, WelM, SalC, nisin) and antibiotics (daptomycin and gramicidin) as well as lipid II cycle-blocking bacteriocins (nisin and Lcn972) and antibiotics (bacitracin). Interestingly, decreased via the SNPs accumulation sensitivity to membrane-active bacteriocins and antibiotics resulted in the concurrently increased vulnerability to bacitracin, carbenicillin, or chlortetracycline. It is suspected that SNPs may result in alterations to the efficiency of the nascent enzymes rather than a total loss of their function as neither deletion nor overexpression of dxsA restored the phenotype observed in spontaneous mutants.

Biophysics meets membrane-active peptides

2008 ◽  
Vol 14 (4) ◽  
pp. 365-367
Author(s):  
Miguel A. R. B. Castanho ◽  
Margitta Dathe
Keyword(s):  
Active Peptides ◽  
Membrane Active Peptides

scholarly journals Staphylococcus aureus Mutants Isolated via Exposure to Nonfluorinated Quinolones: Detection of Known and Unique Mutations

2001 ◽  
Vol 45 (12) ◽  
pp. 3422-3426 ◽  
Author(s):  
Siddhartha Roychoudhury ◽  
Tracy L. Twinem ◽  
Kelly M. Makin ◽  
Mark A. Nienaber ◽  
Chuiying Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Sequence Analysis ◽  
Efflux Pump ◽  
Serial Passage ◽  
Efflux Pump Inhibitor ◽  
In Vitro Development ◽  
Development Of Resistance ◽  
High Level ◽  
Vitro Development

ABSTRACT The in vitro development of resistance to the new nonfluorinated quinolones (NFQs; PGE 9262932, PGE 4175997, and PGE 9509924) was investigated in Staphylococcus aureus. At concentrations two times the MIC, step 1 mutants were isolated more frequently with ciprofloxacin and trovafloxacin (9.1 × 10−8 and 5.7 × 10−9, respectively) than with the NFQs, gatifloxacin, or clinafloxacin (<5.7 × 10−10). Step 2 and step 3 mutants were selected via exposure of a step 1 mutant (selected with trovafloxacin) to four times the MICs of trovafloxacin and PGE 9262932. The step 1 mutant contained the known Ser80-Phe mutation in GrlA, and the step 2 and step 3 mutants contained the known Ser80-Phe and Ser84-Leu mutations in GrlA and GyrA, respectively. Compared to ciprofloxacin, the NFQs were 8-fold more potent against the parent and 16- to 128-fold more potent against the step 3 mutants. Mutants with high-level NFQ resistance (MIC, 32 μg/ml) were isolated by the spiral plater-based serial passage technique. DNA sequence analysis of three such mutants revealed the following mutations: (i) Ser84-Leu in GyrA and Glu84-Lys and His103-Tyr in GrlA; (ii) Ser-84Leu in GyrA, Ser52-Arg in GrlA, and Glu472-Val in GrlB; and (iii) Ser84-Leu in GyrA, Glu477-Val in GyrB, and Glu84-Lys and His103-Tyr in GrlA. Addition of the efflux pump inhibitor reserpine (10 μg/ml) resulted in 4- to 16-fold increases in the potencies of the NFQs against these mutants, whereas it resulted in 2-fold increases in the potencies of the NFQs against the parent.

scholarly journals Antimicrobial Peptides: Mechanisms of Action and Resistance

2016 ◽  
Vol 96 (3) ◽  
pp. 254-260 ◽  
Author(s):  
B. Bechinger ◽  
S.-U. Gorr
Keyword(s):  
Cell Wall ◽  
Cell Membrane ◽  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Rare Event ◽  
Mechanisms Of Action ◽  
Current Evidence ◽  
Aggregation State ◽  
Host Defense Peptides ◽  
Bacterial Membranes

More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide’s structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.

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