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.

scholarly journals Antimicrobial and Antibiofilm Peptides

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 652 ◽  
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.

scholarly journals Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Réka Spohn ◽  
Lejla Daruka ◽  
Viktória Lázár ◽  
Ana Martins ◽  
Fanni Vidovics ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Resistance ◽  
Point Mutations ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Evolutionary Analysis ◽  
Resistance Level ◽  
Wide Range ◽  
Evolution Of Resistance ◽  
Promising Source

Abstract Antimicrobial peptides (AMPs) are promising antimicrobials, however, the potential of bacterial resistance is a major concern. Here we systematically study the evolution of resistance to 14 chemically diverse AMPs and 12 antibiotics in Escherichia coli. Our work indicates that evolution of resistance against certain AMPs, such as tachyplesin II and cecropin P1, is limited. Resistance level provided by point mutations and gene amplification is very low and antibiotic-resistant bacteria display no cross-resistance to these AMPs. Moreover, genomic fragments derived from a wide range of soil bacteria confer no detectable resistance against these AMPs when introduced into native host bacteria on plasmids. We have found that simple physicochemical features dictate bacterial propensity to evolve resistance against AMPs. Our work could serve as a promising source for the development of new AMP-based therapeutics less prone to resistance, a feature necessary to avoid any possible interference with our innate immune system.

scholarly journals Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms

2016 ◽  
Vol 60 (10) ◽  
pp. 6067-6075 ◽  
Author(s):  
Jun Hong ◽  
Jianye Hu ◽  
Fei Ke
Keyword(s):  
Antimicrobial Peptide ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Antibacterial Drug ◽  
Cationic Antimicrobial Peptide ◽  
Content Type ◽  
Tachyplesin I

ABSTRACTTachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms.Aeromonas hydrophilaXS91-4-1,Pseudomonas aeruginosaCGMCC1.2620, andEscherichia coliATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition,P. aeruginosaandE. coliexhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism ofP. aeruginosawas not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity inP. aeruginosa. Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.

The Activity of Alkanna Species in vitro Culture and Intact Plant Extracts Against Antibiotic Resistant Bacteria

2019 ◽  
Vol 25 (16) ◽  
pp. 1861-1865 ◽  
Author(s):  
Naira Sahakyan ◽  
Margarit Petrosyan ◽  
Armen Trchounian
Keyword(s):  
Antibiotic Resistance ◽  
Antibacterial Agents ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistant Bacteria ◽  
Plant Origin ◽  
Bacterial Strains ◽  
Biotechnological Production ◽  
Antibiotic Resistant

Overcoming the antibiotic resistance is nowadays a challenge. There is still no clear strategy to combat this problem. Therefore, the urgent need to find new sources of antibacterial agents exists. According to some literature, substances of plant origin are able to overcome bacterial resistance against antibiotics. Alkanna species plants are among the valuable producers of these metabolites. But there is a problem of obtaining the standardized product. So, this review is focused on the discussion of the possibilities of biotechnological production of antimicrobial agents from Alkanna genus species against some microorganisms including antibiotic resistant bacterial strains.

scholarly journals Determining the Rate of Development of Antibiotic Resistance to Streptomycin and Doxycycline in Escherichia coli

2019 ◽  
pp. 2-7
Author(s):  
Dominique Tertigas ◽  
Gemma Barber
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Combination Treatment ◽  
Bacterial Resistance ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Small Scale ◽  
Rate Of Development ◽  
E Coli ◽  
Successive Generations

Antibiotic resistance is a pressing issue in the medical field today. It is important to understand the development of bacterial resistance to implement effective preventative measures against antibiotic resistant bacteria. This study investigated the rate at which Escherichia coli (E. coli), a common pathogen, developed resistance to streptomycin and doxycycline, as Oz et al. (2014) showed differing levels of resistance in E. coli to these two antibiotics. The development of antibiotic resistance was measured by adding E. coli to 96-well plates in the presence of increasing doses of doxycycline, streptomycin, or a combination treatment. Successive generations were added to the same treatments to see whether they would grow at higher concentrations of antibiotic. The change in minimum inhibitory concentration for streptomycin and doxycycline was determined as the bacteria became increasingly resistant to each antibiotic. The fastest rate of antibiotic resistance was observed for streptomycin, with doxycycline resistance exhibiting a slower rate of development. The rate of resistance development for the combination treatment was the slowest, potentially due to small differences in target domains. Some cross-resistance was also observed. This study provides a small-scale methodological basis and preliminary insight on antibiotic resistance trends for two antibiotic classes and a combination treatment.

scholarly journals Evolution of Bacterial Cross-Resistance to Lytic Phages and Albicidin Antibiotic

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaitlyn E. Kortright ◽  
Simon Doss-Gollin ◽  
Benjamin K. Chan ◽  
Paul E. Turner
Keyword(s):  
Bacterial Resistance ◽  
Phage Therapy ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Wild Type ◽  
E Coli ◽  
High Resource ◽  
Bacterial Mutants ◽  
Global Increase ◽  
Evolutionary Consequences

Due to concerns over the global increase of antibiotic-resistant bacteria, alternative antibacterial strategies, such as phage therapy, are increasingly being considered. However, evolution of bacterial resistance to new therapeutics is almost a certainty; indeed, it is possible that resistance to alternative treatments might result in an evolved trade-up such as enhanced antibiotic resistance. Here, we hypothesize that selection for Escherichia coli bacteria to resist phage T6, phage U115, or albicidin, a DNA gyrase inhibitor, should often result in a pleiotropic trade-up in the form of cross-resistance, because all three antibacterial agents interact with the Tsx porin. Selection imposed by any one of the antibacterials resulted in cross-resistance to all three of them, in each of the 29 spontaneous bacterial mutants examined in this study. Furthermore, cross-resistance did not cause measurable fitness (growth) deficiencies for any of the bacterial mutants, when competed against wild-type E. coli in both low-resource and high-resource environments. A combination of whole-genome and targeted sequencing confirmed that mutants differed from wild-type E. coli via change(s) in the tsx gene. Our results indicate that evolution of cross-resistance occurs frequently in E. coli subjected to independent selection by phage T6, phage U115 or albicidin. This study cautions that deployment of new antibacterial therapies such as phage therapy, should be preceded by a thorough investigation of evolutionary consequences of the treatment, to avoid the potential for evolved trade-ups.

Nanoantibiotics: A Novel Rational Approach to Antibiotic Resistant Infections

2019 ◽  
Vol 20 (9) ◽  
pp. 720-741 ◽  
Author(s):  
Ayse Basak Engin ◽  
Atilla Engin
Keyword(s):  
Drug Resistance ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Multiple Drug Resistance ◽  
Rational Approach ◽  
Resistant Bacteria ◽  
Multiple Drug ◽  
Stimuli Responsive ◽  
Conventional Antibiotics ◽  
Multiple Drugs

Background: The main drawbacks for using conventional antimicrobial agents are the development of multiple drug resistance due to the use of high concentrations of antibiotics for extended periods. This vicious cycle often generates complications of persistent infections, and intolerable antibiotic toxicity. The problem is that while all new discovered antimicrobials are effective and promising, they remain as only short-term solutions to the overall challenge of drug-resistant bacteria. Objective: Recently, nanoantibiotics (nAbts) have been of tremendous interest in overcoming the drug resistance developed by several pathogenic microorganisms against most of the commonly used antibiotics. Compared with free antibiotic at the same concentration, drug delivered via a nanoparticle carrier has a much more prominent inhibitory effect on bacterial growth, and drug toxicity, along with prolonged drug release. Additionally, multiple drugs or antimicrobials can be packaged within the same smart polymer which can be designed with stimuli-responsive linkers. These stimuli-responsive nAbts open up the possibility of creating multipurpose and targeted antimicrobials. Biofilm formation still remains the leading cause of conventional antibiotic treatment failure. In contrast to conventional antibiotics nAbts easily penetrate into the biofilm, and selectively target biofilm matrix constituents through the introduction of bacteria specific ligands. In this context, various nanoparticles can be stabilized and functionalized with conventional antibiotics. These composites have a largely enhanced bactericidal efficiency compared to the free antibiotic. Conclusion: Nanoparticle-based carriers deliver antibiotics with better biofilm penetration and lower toxicity, thus combating bacterial resistance. However, the successful adaptation of nanoformulations to clinical practice involves a detailed assessment of their safety profiles and potential immunotoxicity.

Understanding membrane-active antimicrobial peptides

2017 ◽  
Vol 50 ◽  
Author(s):  
Huey W. Huang ◽  
Nicholas E. Charron
Keyword(s):  
Antimicrobial Peptides ◽  
Soft Matter ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Molecular Structures ◽  
Membrane Domain ◽  
Defense Proteins ◽  
Bacterial Membranes

AbstractBacterial membranes represent an attractive target for the design of new antibiotics to combat widespread bacterial resistance to traditional inhibitor-based antibiotics. Understanding how antimicrobial peptides (AMPs) and other membrane-active agents attack membranes could facilitate the design of new, effective antimicrobials. AMPs, which are small, gene-encoded host defense proteins, offer a promising basis for the study of membrane-active antimicrobial agents. These peptides are cationic and amphipathic, spontaneously binding to bacterial membranes and inducing transmembrane permeability to small molecules. Yet there are often confusions surrounding the details of the molecular mechanisms of AMPs. Following the doctrine of structure–function relationship, AMPs are often viewed as the molecular scaffolding of pores in membranes. Instead we believe that the full mechanism of AMPs is understandable if we consider the interactions of AMPs with the whole membrane domain, where interactions induce structural transformations of the entire membrane, rather than forming localized molecular structures. We believe that it is necessary to consider the entire soft matter peptide-membrane system as it evolves through several distinct states. Accordingly, we have developed experimental techniques to investigate the state and structure of the membrane as a function of the bound peptide to lipid ratio, exactly as AMPs in solution progressively bind to the membrane and induce structural changes to the entire system. The results from these studies suggest that global interactions of AMPs with the membrane domain are of fundamental importance to understanding the antimicrobial mechanisms of AMPs.

scholarly journals Investigation of the Potential for Mutational Resistance to XF-73, Retapamulin, Mupirocin, Fusidic Acid, Daptomycin, and Vancomycin in Methicillin-ResistantStaphylococcus aureusIsolates during a 55-Passage Study

2010 ◽  
Vol 55 (3) ◽  
pp. 1177-1181 ◽  
Author(s):  
David J. Farrell ◽  
Marion Robbins ◽  
William Rhys-Williams ◽  
William G. Love
Keyword(s):  
Staphylococcus Aureus ◽  
Fusidic Acid ◽  
Bacterial Resistance ◽  
Point Mutations ◽  
Hospital Setting ◽  
Fold Increase ◽  
Cross Resistance ◽  
Resistant Bacteria ◽  
Sequencing Analysis ◽  
Antibacterial Drugs

ABSTRACTXF-73 is a dicationic porphyrin drug with rapid Gram-positive antibacterial activity currently undergoing clinical trials for the nasal decolonization ofStaphylococcus aureus, including methicillin-resistantStaphylococcus aureus(MRSA). In multistep (55-passage) resistance selection studies in the presence of subinhibitory concentrations of XF-73, retapamulin, mupirocin, fusidic acid, and vancomycin against four Network on Antimicrobial Resistance inStaphylococcus aureusMRSA strains, there was no >4-fold increase in the MIC for XF-73 after 55 passages. In contrast, there was an increase in the MICs for retapamulin (from 0.25 μg/ml to 4 to 8 μg/ml), for mupirocin (from 0.12 μg/ml to 16 to 512 μg/ml), for fusidic acid (from 0.12 μg/ml to 256 μg/ml), and for vancomycin (from 1 μg/ml to 8 μg/ml in two of the four strains tested). Further investigations usingS. aureusNRS384 (USA300) and daptomycin demonstrated a 64-fold increase in the MIC after 55 passages (from 0.5 μg/ml to 32 μg/ml) with a >4-fold increase in the MIC obtained after only five passages. Sequencing analysis of selected isolates confirmed previously reported point mutations associated with daptomycin resistance. No cross-resistance to XF-73 was observed with the daptomycin-resistant strains, suggesting that whereas the two drugs act on the bacterial cell membrane, their specific site of action differs. XF-73 thus represents the first in a new class of antibacterial drugs, which (unlike the comparator antibiotics) after 55 passages exhibited a ≤4-fold increase in MIC against the strains tested. Antibacterial drugs with a low propensity for inducing bacterial resistance are much needed for the prevention and treatment of multidrug-resistant bacteria both within and outside the hospital setting.

Antibiotic Cycling and Marketing Into the 21st Century: A Perspective From the Pharmaceutical Industry

2000 ◽  
Vol 21 (S1) ◽  
pp. S32-S35 ◽  
Author(s):  
Bruce S. Lavin
Keyword(s):  
Antimicrobial Resistance ◽  
Pharmaceutical Industry ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Medical Community ◽  
Resistant Bacteria ◽  
Environmental Pressures ◽  
Development Of Resistance ◽  
Antibiotic Cycling

AbstractBefore the development of the first antimicrobial agents, bacteria already had demonstrated an ability to adapt to stress in the environment, resulting in the development of resistance that often makes the prevailing antibiotic treatment ineffective. The response to antimicrobial resistance in the medical community has been to use new or alternative antibiotics not previously used against the resistant bacteria. The pharmaceutical industry has responded to the resistance problem by producing newer antibiotics, either as modifications of currently existing compounds or as combinations of compounds that may inhibit or bypass the bacterial resistance mechanisms. The development of new antibiotics is a lengthy and costly process. To be successful, the pharmaceutical industry must anticipate the changing needs of the medical community, as well as the dynamic process of antimicrobial resistance. The marketing of new antimicrobial agents must be adaptable to the potential environmental pressures that induce bacterial resistance in order to ensure the longevity of the agents.

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