ReviewGlycopeptide resistance: Links with inorganic phosphate metabolism and cell envelope stress
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Introduction: the problem of antibiotic resistance
In recent years the world has been facing two important and linked problems: i) the emergence and spread of antibiotic resistance in pathogenic bacteria and ii) failure to discover new chemotherapeutic agents. Antibiotic resistance in pathogenic bacteria does not only generate an important economic burden for the healthcare system, but also reduces the efficacy of antibiotics and increases mortality. Thus, antibiotic resistance is considered a worldwide threat for human health, since once
Cell-wall as an antibiotic target
The majority of antimicrobials used currently target the bacterial DNA, RNA, protein or cell-wall biosynthesis. In this section we will focus on drugs acting on the biosynthesis of the main component of the cell-wall, peptidoglycan (PG). PG is a polymer composed of glycan strands crosslinked by peptides. These glycan strands are formed by alternating units of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). MurNAc is associated with peptides responsible for crosslinking the PG
Glycopeptides: a very important class of antibiotics
Glycopeptide antibiotics are highly important for the treatment of infections caused by Gram-positive bacteria, and usually represent the only treatment for infections caused by multi drug-resistant strains of enterococci, streptococci and staphylococci. In fact, the two main glycopeptides, vancomycin and teicoplanin, are widely used in the treatment of MRSA and penicillin-resistant S. pneumoniae.
Antibiotics from this family share a common heptapeptide structure and are synthetised by
Main glycopeptide antibiotics
Vancomycin was discovered in 1955 at Eli Lilly (Indianapolis, USA), constituting the first member of the glycopeptides family [58]. It was approved for the use of penicillin-resistant staphylococcal infections by the FDA in 1958. The use of vancomycin started to increase in the early 1980s, rising rapidly during the 1980s and early 1990s [59]. The first attempts to reduce its use in response to the spread of vancomycin-resistant bacteria resulted in a slight decline in use after 1994.
Mechanisms of glycopeptide resistance and transcriptional regulation
The unique mode of action of glycopeptide antibiotics was promising and therefore a slow development of resistances in pathogenic bacteria was expected. In fact, it took over 30 years after the introduction into the clinic to find the first vancomycin-resistant enterococci (VRE) strains [72], [73]. This is a very long period in comparison to the emergence of other cases of antibiotic resistance. Nowadays, VRE have become significant nosocomial pathogens worldwide, mainly due to their
Pho regulon: a phosphate dependent global response
Inorganic phosphate (Pi) is an essential nutrient that forms part of many of the key components within the cell, such as nucleic acids or phospholipids. Pi is involved in many important cellular processes, including energy metabolism and intracellular signalling. Despite the essentiality of Pi for life, this nutrient is normally found at very low concentrations in its free form in the environment, especially in soils. To adapt and survive in Pi scarcity, bacteria have evolved an array of
Links between the Pho regulon and pathogenesis
Bacterial pathogens of humans, animals and plants normally have to adapt to Pi-limiting and/or Pi-rich environments in the host depending on the site of infection. There are numerous studies that report links between Pi regulation and pathogenesis; see the following references [110], [111], [112] for details.
The Pho regulon can influence virulence by increasing toxin production, biofilm formation, acid tolerance and resistance to antimicrobial compounds, among other processes. In some bacteria,
Glycopeptide resistance is highly influenced by Pi
A considerable number of studies have reported that the biosynthesis of most antibiotics is regulated by Pi; reviewed by Martín [121]. There are also studies that establish links between Pi regulation and antibiotic resistance. For instance, oxytetracycline production in Streptomyces rimosus and its corresponding resistance events seem to have a simple mechanism of Pi regulation, which ensures that resistance to the produced antibiotic increases in proportion to its biosynthesis [122]. In
D-alanylation of cell-wall components and Pi control: teichoic acids
The peptidoglycan layers protect Gram-positive bacteria from osmotic lysis and constitute a barrier against toxic compounds [137]. As described before, peptidoglycan also functions as a scaffold for the attachment of proteins, capsular polysaccharides and wall teichoic acids (WTAs). In order to save Pi, some bacteria are able to replace the Pi-rich WTAs with Pi-free teichuronic acids. This process is regulated by PhoP, which in B. subtilis initiates teichuronic acid synthesis under Pi
a) Cell envelope stress
As described before, resistance to vancomycin can be acquired by several different mechanisms. The most common involves conversion of cell-wall precursors ending in D-Ala-D-Ala to D-Ala-D-Lac or D-Ala-D-Ser [146]. Another mechanism by which resistance can be acquired is through mutation of sigma factors and endogenous two-component signal transduction systems that control normal cell-wall metabolism (such as WalRK), or the cellular response to cell-wall damage, like VraRS and GraRS [147], [148]
Future perspectives
The phenomenon of antimicrobial resistance is a critical health issue today as the World Health Organization currently recognizes. Indeed, most bacteria have developed some level of resistance to antibiotics. Worse still is the fact that many clinically important pathogens have developed resistance to many, or even all, available antibiotics. The problem of antimicrobial resistance is further complicated by the continued, decades long, lack of significant numbers of novel antimicrobials in drug
Acknowledgments
We thank David Roberts (Newcastle University) for performing a spell check and making constructive comments about the manuscript. We thank Paloma Liras for useful scientific discussions.
References (175)
- et al.
A resistant pneumococcus
Lancet
(1967) - et al.
Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study
Lancet Infect. Dis.
(2016) - et al.
Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial
Lancet Infect. Dis.
(2012) - et al.
4-Thiazolidinones: novel inhibitors of the bacterial enzyme MurB
Bioorg. Med. Chem. Lett.
(2000) - et al.
Discovery of the first antibacterial small molecule inhibitors of MurB
Bioorg. Med. Chem. Lett.
(2003) - et al.
Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis
Lancet. Infect. Dis.
(2010) - et al.
Synthesis of the nucleoside moiety of liposidomycins: elucidation of the pharmacophore of this family of MraY inhibitors
Bioorg. Med. Chem. Lett.
(2000) - et al.
Identification of novel inhibitors of phospho-MurNAc-pentapeptide translocase MraY from library screening: isoquinoline alkaloid michellamine B and xanthene dye phloxine B
Bioorg. Med. Chem.
(2014) - et al.
Development of bacterial transglycosylase inhibitors as new antibiotics: moenomycin A treatment for drug-resistant Helicobacter pylori
Bioorg. Med. Chem. Lett.
(2014) - et al.
Multicomponent antibiotic substances produced by fermentation: implications for regulatory authorities, critically ill patients and generics
Int. J. Antimicrob. Agents
(2014)
Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI Study
Int. J. Antimicrob. Agents
Vancomycin and oritavancin have different modes of action in Enterococcus faecium
J. Mol. Biol.
Glycopeptide resistance in enterococci
Trends Microbiol.
Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus
FEMS Microbiol. Lett.
Mechanism of action of oritavancin and related glycopeptide antibiotics
FEMS Microbiol. Rev.
Cell permeable vanX inhibitors as vancomycin re-sensitizing agents
Bioorg. Med. Chem. Lett.
Insertional inactivation of a gene which controls expression of vancomycin resistance on plasmid pHKK100
FEMS Microbiol. Lett.
Regulation of the pho regulon of Escherichia coli K-12. Cloning of the regulatory genes phoB and phoR and identification of their gene products
J. Mol. Biol.
Cross-talk between the histidine protein kinase VanS and the response regulator PhoB, Characterization and identification of a VanS domain that inhibits activation of PhoB
J. Biol. Chem.
Antibacterial drug discovery in the resistance era
Nature
On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenza
Br. J. Exp. Pathol.
Resistance to antibiotics targeted to the bacterial cell-wall
Protein Sci.
First detection of the mcr-1 colistin resistance gene in Escherichia coli in Italy
Antimicrob. Agents Chemother.
Dissemination of antimicrobial resistance in microbial ecosystems through horizontal gene transfer
Front. Microbiol.
Isolation of pre-adaptive mutants in bacteria by sib selection
Genetics
Antibiotic resistance is ancient
Nature
Antibiotic resistance is prevalent in an isolated cave microbiome
PLoS ONE
Review on Antimicrobial Resistance. Tackling a Crisis for the Health and Wealth of Nations
Fidaxomicin versus vancomycin for Clostridium difficile infection
N. Engl. J. Med.
A 1000-year-old antimicrobial remedy with antistaphylococcal activity
MBio
Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE
J. Infect. Dis.
Kisameet clay exhibits potent antibacterial activity against the ESKAPE pathogens
MBio
Peptidoglycan structure and architecture
FEMS Microbiol. Rev.
Structural variation in the glycan strands of bacterial peptidoglycan
FEMS Microbiol. Rev.
Cytoplasmic steps of peptidoglycan biosynthesis
FEMS Microbiol. Rev.
The biosynthesis of peptidoglycan lipid-linked intermediates
FEMS Microbiol. Rev.
Lipid flippases for bacterial peptidoglycan biosynthesis
Lipid Insights
The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis
FEMS Microbiol. Rev.
Viable screening targets related to the bacterial cell-wall
Ann. NY Acad. Sci.
The mechanism of action of fosfomycin (phosphonomycin)
Ann. NY Acad. Sci.
MurF inhibitors with antibacterial activity: effect on muropeptide levels
Antimicrob. Agents Chemother.
MreB and MurG as scaffolds for the cytoplasmic steps of peptidoglycan biosynthesis
Environ. Microbiol.
Neurochemical studies with l-cycloserine, a central depressant agent
J. Neurochem.
Adverse neurological reactions in patients with multidrug-resistant pulmonary tuberculosis after coadministration of cycloserine and ofloxacin
Clin. Infect. Dis.
The role of lipid-linked saccharides in the biosynthesis of complex carbohydrates
Annu. Rev. Plant Physiol.
Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins
Antimicrob. Agents Chemother.
Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo
J. Antimicrob. Chemother.
Effects of moenomycin on Escherichia coli
J. Gen. Microbiol.
Ramoplanin inhibits bacterial transglycosylases by binding as a dimer to lipid II
J. Am. Chem. Soc.
The potential for emerging therapeutic options for Clostridium difficile infection
Gut Microbes
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