Elsevier

Biochemical Pharmacology

Volume 133, 1 June 2017, Pages 74-85
Biochemical Pharmacology

Review
Glycopeptide resistance: Links with inorganic phosphate metabolism and cell envelope stress

https://doi.org/10.1016/j.bcp.2016.11.017Get rights and content

Abstract

Antimicrobial resistance is a critical health issue today. Many pathogens have become resistant to many or all available antibiotics and limited new antibiotics are in the pipeline. Glycopeptides are used as a ‘last resort’ antibiotic treatment for many bacterial infections, but worryingly, glycopeptide resistance has spread to very important pathogens such as Enterococcus faecium and Staphylococcus aureus. Bacteria confront multiple stresses in their natural environments, including nutritional starvation and the action of cell-wall stressing agents. These stresses impact bacterial susceptibility to different antimicrobials. This article aims to review the links between glycopeptide resistance and different stresses, especially those related with cell-wall biosynthesis and inorganic phosphate metabolism, and to discuss promising alternatives to classical antibiotics to avoid the problem of antimicrobial resistance.

Section snippets

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)

  • J.A. Roberts et al.

    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

    (2014)
  • G.J. Patti et al.

    Vancomycin and oritavancin have different modes of action in Enterococcus faecium

    J. Mol. Biol.

    (2009)
  • M. Arthur et al.

    Glycopeptide resistance in enterococci

    Trends Microbiol.

    (1996)
  • W.C. Noble et al.

    Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus

    FEMS Microbiol. Lett.

    (1992)
  • N.E. Allen et al.

    Mechanism of action of oritavancin and related glycopeptide antibiotics

    FEMS Microbiol. Rev.

    (2003)
  • R. Muthyala et al.

    Cell permeable vanX inhibitors as vancomycin re-sensitizing agents

    Bioorg. Med. Chem. Lett.

    (2014)
  • S. Handwerger et al.

    Insertional inactivation of a gene which controls expression of vancomycin resistance on plasmid pHKK100

    FEMS Microbiol. Lett.

    (1992)
  • J. Tommassen et al.

    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.

    (1982)
  • S.L. Fisher et al.

    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.

    (1995)
  • E.D. Brown et al.

    Antibacterial drug discovery in the resistance era

    Nature

    (2016)
  • A. Fleming

    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.

    (1929)
  • I. Nikolaidis et al.

    Resistance to antibiotics targeted to the bacterial cell-wall

    Protein Sci.

    (2014)
  • A. Cannatelli et al.

    First detection of the mcr-1 colistin resistance gene in Escherichia coli in Italy

    Antimicrob. Agents Chemother.

    (2016)
  • C.J.H. von Wintersdorff et al.

    Dissemination of antimicrobial resistance in microbial ecosystems through horizontal gene transfer

    Front. Microbiol.

    (2016)
  • L.L. Cavalli-Sforza et al.

    Isolation of pre-adaptive mutants in bacteria by sib selection

    Genetics

    (1956)
  • V.M. D’Costa et al.

    Antibiotic resistance is ancient

    Nature

    (2011)
  • K. Bhullar et al.

    Antibiotic resistance is prevalent in an isolated cave microbiome

    PLoS ONE

    (2012)
  • J. O’Neill

    Review on Antimicrobial Resistance. Tackling a Crisis for the Health and Wealth of Nations

    (2014)
  • T.J. Louie et al.

    Fidaxomicin versus vancomycin for Clostridium difficile infection

    N. Engl. J. Med.

    (2011)
  • F. Harrison et al.

    A 1000-year-old antimicrobial remedy with antistaphylococcal activity

    MBio

    (2015)
  • L.B. Rice

    Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE

    J. Infect. Dis.

    (2008)
  • S. Behroozian et al.

    Kisameet clay exhibits potent antibacterial activity against the ESKAPE pathogens

    MBio

    (2016)
  • W. Vollmer et al.

    Peptidoglycan structure and architecture

    FEMS Microbiol. Rev.

    (2008)
  • W. Vollmer

    Structural variation in the glycan strands of bacterial peptidoglycan

    FEMS Microbiol. Rev.

    (2008)
  • H. Barreteau et al.

    Cytoplasmic steps of peptidoglycan biosynthesis

    FEMS Microbiol. Rev.

    (2008)
  • A. Bouhss et al.

    The biosynthesis of peptidoglycan lipid-linked intermediates

    FEMS Microbiol. Rev.

    (2008)
  • N. Ruiz

    Lipid flippases for bacterial peptidoglycan biosynthesis

    Lipid Insights

    (2015)
  • E. Sauvage et al.

    The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis

    FEMS Microbiol. Rev.

    (2008)
  • L.L. Silver

    Viable screening targets related to the bacterial cell-wall

    Ann. NY Acad. Sci.

    (2013)
  • F.M. Kahan et al.

    The mechanism of action of fosfomycin (phosphonomycin)

    Ann. NY Acad. Sci.

    (1974)
  • E.Z. Baum et al.

    MurF inhibitors with antibacterial activity: effect on muropeptide levels

    Antimicrob. Agents Chemother.

    (2009)
  • S. Favini-Stabile et al.

    MreB and MurG as scaffolds for the cytoplasmic steps of peptidoglycan biosynthesis

    Environ. Microbiol.

    (2013)
  • P. Scotto et al.

    Neurochemical studies with l-cycloserine, a central depressant agent

    J. Neurochem.

    (1963)
  • W.W. Yew et al.

    Adverse neurological reactions in patients with multidrug-resistant pulmonary tuberculosis after coadministration of cycloserine and ofloxacin

    Clin. Infect. Dis.

    (1993)
  • A.D. Elbein

    The role of lipid-linked saccharides in the biosynthesis of complex carbohydrates

    Annu. Rev. Plant Physiol.

    (1979)
  • M. Inukai et al.

    Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins

    Antimicrob. Agents Chemother.

    (1993)
  • T. Koga et al.

    Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo

    J. Antimicrob. Chemother.

    (2004)
  • Y. van Heijenoort et al.

    Effects of moenomycin on Escherichia coli

    J. Gen. Microbiol.

    (1987)
  • Y. Hu et al.

    Ramoplanin inhibits bacterial transglycosylases by binding as a dimer to lipid II

    J. Am. Chem. Soc.

    (2003)
  • H. Mathur et al.

    The potential for emerging therapeutic options for Clostridium difficile infection

    Gut Microbes

    (2014)
  • View full text