Glycopeptide antibiotic analogs efficient against vancomycin-resistant bacteria: a patent evaluation (WO2013022763)

2013 ◽  
Vol 23 (12) ◽  
pp. 1625-1634
Author(s):  
Eugenia N Olsufyeva ◽  
Maria N Preobrazhenskaya
Keyword(s):  
Resistant Bacteria ◽  
Glycopeptide Antibiotic ◽  
Patent Evaluation ◽  
Vancomycin Resistant

Opposite effect of vancomycin and D-Cycloserine combination in both vancomycin resistant Staphylococcus aureus and enterococci

2020 ◽  
Vol 367 (8) ◽  
Author(s):  
Abdelhakim Boudrioua ◽  
Yanyan Li ◽  
Axel Hartke ◽  
Caroline Giraud
Keyword(s):  
Staphylococcus Aureus ◽  
Opposite Effect ◽  
Inhibitory Concentration ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Glycopeptide Antibiotic ◽  
Antibiotic Resistant ◽  
Peptidoglycan Biosynthesis ◽  
Vancomycin Resistant ◽  
Type Strains

ABSTRACT The increasing spread of antibiotic resistant bacteria is a major human health concern. The challenging development of new effective antibiotics has led to focus on seeking synergistic antibiotic combinations. Vancomycin (VAN) is a glycopeptide antibiotic used to treat Staphylococcus aureus and enterococci infections. It is targeting D-Alanyl-D-Alanine dimers during peptidoglycan biosynthesis. D-cycloserine (DCS) is a D-Alanine analogue that targets peptidoglycan biosynthesis by inhibiting D-Alanine:D-Alanine ligase (Ddl). The VAN-DCS combination was found to be synergistic in VAN resistant S. aureus strains lacking van genes cluster. We hypothesize that this combination leads to opposite effects in S. aureus and enterococci strains harboring van genes cluster where VAN resistance is conferred by the synthesis of modified peptidoglycan precursors ending in D-Alanyl-D-Lactate. The calculated Fractional Inhibitory Concentration of VAN-DCS combination in a van- vancomycin-intermediate, VanA type, and VanB type strains were 0.5, 5 and 3, respectively. As a result, VAN-DCS combination leads to synergism in van-lacking strains, and to antagonism in strains harboring van genes cluster. The VAN-DCS antagonism is due to a mechanism that we named van-mediated Ddl inhibition bypass. Our results show that antibiotic combinations can lead to opposite effects depending on the genetic backgrounds.

scholarly journals Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic.

1996 ◽  
Vol 40 (10) ◽  
pp. 2356-2362 ◽  
Author(s):  
N E Allen ◽  
J N Hobbs ◽  
T I Nicas
Keyword(s):  
Late Stage ◽  
Substrate Inhibition ◽  
Resistant Bacteria ◽  
Cross Linking ◽  
Glycopeptide Antibiotic ◽  
Peptidoglycan Biosynthesis ◽  
Aerococcus Viridans ◽  
Muramyl Peptide ◽  
Peptide Precursors ◽  
Vancomycin Resistant

LY191145 is a p-chlorobenzyl derivative of LY264826 (A82846B) with activity against both vancomycin-susceptible and -resistant enterococci. Incorporation of L-[14C]lysine into peptidoglycan of intact vancomycin-susceptible and -resistant Enterococcus faecium was inhibited by LY191145 (50% inhibitory concentrations of 1 and 5 microgram/ml, respectively). Inhibition was accompanied by accumulation of UDP-muramyl-peptide precursors in the cytoplasm. This agent inhibited late-stage steps in peptidoglycan biosynthesis in permeabilized E. faecium when either the UDP-muramyl-pentapeptide precursor from vancomycin-susceptible E. faecium or the UDP-muramyl-pentadepsipeptide precursor from vancomycin-resistant E. faecium was used as a substrate. Inhibition of late-stage steps led to accumulation of an N-acetyl-[14C]glucosamine-labeled lipid intermediate indicative of inhibition of the transglycosylation step. Inhibition of peptidoglycan polymerization without affecting cross-linking in a particulate membrane-plus-wall-fragment assay from Aerococcus viridans was consistent with this explanation. The fact that inhibition of peptidoglycan biosynthesis by LY191145 was not readily antagonized by an excess of free acyl-D-alanyl-D-alanine or acyl-D-alanyl-D-lactate ligands indicates that the manner in which this compound inhibits transglycosylation may not be identical to that of vancomycin.

scholarly journals The First Dimeric Derivatives of the Glycopeptide Antibiotic Teicoplanin

2022 ◽  
Vol 15 (1) ◽  
pp. 77
Author(s):  
Ilona Bereczki ◽  
Zsolt Szűcs ◽  
Gyula Batta ◽  
Tamás Milán Nagy ◽  
Eszter Ostorházi ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
High Activity ◽  
Parent Compound ◽  
Resistant Bacteria ◽  
Glycopeptide Antibiotic ◽  
Bacterial Strains ◽  
Vancomycin Resistant Enterococci ◽  
Vancomycin Resistant ◽  
Cobalt Coordination ◽  
Derivatives Of

Various dimeric derivatives of the glycopeptide antibiotic teicoplanin were prepared with the aim of increasing the activity of the parent compound against glycopeptide-resistant bacteria, primarily vancomycin-resistant enterococci. Starting from teicoplanin, four covalent dimers were prepared in two orientations, using an α,ω-bis-isothiocyanate linker. Formation of a dimeric cobalt coordination complex of an N-terminal L-histidyl derivative of teicoplanin pseudoaglycone has been detected and its antibacterial activity evaluated. The Co(III)-induced dimerization of the histidyl derivative was demonstrated by DOSY experiments. Both the covalent and the complex dimeric derivatives showed high activity against VanA teicoplanin-resistant enterococci, but their activity against other tested bacterial strains did not exceed that of the monomeric compounds.

scholarly journals Multiresistant Bacteria Isolated from Intestinal Faeces of Farm Animals in Austria

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 466
Author(s):  
Herbert Galler ◽  
Josefa Luxner ◽  
Christian Petternel ◽  
Franz F. Reinthaler ◽  
Juliana Habib ◽  
...  
Keyword(s):  
Meat Products ◽  
Animal Husbandry ◽  
Multidrug Resistant ◽  
Farm Animals ◽  
Resistant Bacteria ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
E Coli ◽  
Multiresistant Bacteria ◽  
Vancomycin Resistant

In recent years, antibiotic-resistant bacteria with an impact on human health, such as extended spectrum β-lactamase (ESBL)-containing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), have become more common in food. This is due to the use of antibiotics in animal husbandry, which leads to the promotion of antibiotic resistance and thus also makes food a source of such resistant bacteria. Most studies dealing with this issue usually focus on the animals or processed food products to examine the antibiotic resistant bacteria. This study investigated the intestine as another main habitat besides the skin for multiresistant bacteria. For this purpose, faeces samples were taken directly from the intestines of swine (n = 71) and broiler (n = 100) during the slaughter process and analysed. All samples were from animals fed in Austria and slaughtered in Austrian slaughterhouses for food production. The samples were examined for the presence of ESBL-producing Enterobacteriaceae, MRSA, MRCoNS and VRE. The resistance genes of the isolated bacteria were detected and sequenced by PCR. Phenotypic ESBL-producing Escherichia coli could be isolated in 10% of broiler casings (10 out of 100) and 43.6% of swine casings (31 out of 71). In line with previous studies, the results of this study showed that CTX-M-1 was the dominant ESBL produced by E. coli from swine (n = 25, 83.3%) and SHV-12 from broilers (n = 13, 81.3%). Overall, the frequency of positive samples with multidrug-resistant bacteria was lower than in most comparable studies focusing on meat products.

scholarly journals Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2888 ◽  
Author(s):  
Buthaina Jubeh ◽  
Zeinab Breijyeh ◽  
Rafik Karaman
Keyword(s):  
Turning Point ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Medical Interventions ◽  
Gram Positive Bacteria ◽  
New Antibiotics ◽  
Vancomycin Resistant ◽  
New Treatments ◽  
Emergence Of Resistance

The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.

scholarly journals Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

2019 ◽  
Vol 20 (6) ◽  
pp. 1255 ◽  
Author(s):  
Ana Monserrat-Martinez ◽  
Yann Gambin ◽  
Emma Sierecki
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Rational Design ◽  
Disease Onset ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Antibiotic Discovery

Since their discovery in the early 20th century, antibiotics have been used as the primary weapon against bacterial infections. Due to their prophylactic effect, they are also used as part of the cocktail of drugs given to treat complex diseases such as cancer or during surgery, in order to prevent infection. This has resulted in a decrease of mortality from infectious diseases and an increase in life expectancy in the last 100 years. However, as a consequence of administering antibiotics broadly to the population and sometimes misusing them, antibiotic-resistant bacteria have appeared. The emergence of resistant strains is a global health threat to humanity. Highly-resistant bacteria like Staphylococcus aureus (methicillin-resistant) or Enterococcus faecium (vancomycin-resistant) have led to complications in intensive care units, increasing medical costs and putting patient lives at risk. The appearance of these resistant strains together with the difficulty in finding new antimicrobials has alarmed the scientific community. Most of the strategies currently employed to develop new antibiotics point towards novel approaches for drug design based on prodrugs or rational design of new molecules. However, targeting crucial bacterial processes by these means will keep creating evolutionary pressure towards drug resistance. In this review, we discuss antibiotic resistance and new options for antibiotic discovery, focusing in particular on new alternatives aiming to disarm the bacteria or empower the host to avoid disease onset.

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