Trends in Biotechnology
Volume 28, Issue 12, December 2010, Pages 596-604
Journal home page for Trends in Biotechnology

Review
β-Lactam and glycopeptide antibiotics: first and last line of defense?

https://doi.org/10.1016/j.tibtech.2010.09.004Get rights and content

Most infections are caused by bacteria, many of which are ever-evolving and resistant to nearly all available antibiotics. β-Lactams and glycopeptides are used to combat these infections by inhibiting bacterial cell-wall synthesis. This mechanism remains an interesting target in the search for new antibiotics in light of failed genomic approaches and the limited input of major pharmaceutical companies. Several strategies have enriched the pipeline of bacterial cell-wall inhibitors; examples include combining screening strategies with lesser-explored microbial diversity, or reinventing known scaffolds based on structure-function relationships. Drugs developed using novel strategies will contribute to the arsenal in fight against the continued emergence of bacterial resistance.

Section snippets

The occurrence of resistance

Since the discovery of penicillin, β-lactam antibiotics, which contain a β-lactam nucleus in their molecular structure, are the first choice in treating bacterial infections. Most penicillins and cephalosporins prescribed today are chemical derivatives of the natural scaffold produced by microorganisms. β-Lactams share the same mode of action, inhibiting synthesis of the bacterial cell wall by covalently binding with nucleophilic active site serine residues in d,d-transpeptidases (also called

Glycopeptide resistance

Vancomycin resistance has appeared in common hospital bacteria that are normally found in the human gut (e.g. enterococci) [21]. The potential of the spread of vancomycin resistance has prompted researchers to apply the term crisis for vancomycin-resistant S. aureus (VRSA) [22]. Indeed, in 1996, signs of VRSA were noted in patients hospitalized in three geographically different locations [23]. In 2002, highly resistant VRSA strains were isolated following in vivo horizontal resistant-gene

Need for new antibiotics

The ever-increasing need for a new generation of antibiotics capable of combating evolving pathogens is aggravated because the current portfolio of compounds in clinical trials consists largely of derivatives of chemical classes for which there are already underlying resistance mechanisms. A remarkable innovation gap of almost 40 years between the introduction of quinolones and streptogramins in the early 1960s and approval of the next new structural antibiotic classes, the oxazolidinone

Still targeting the cell wall

Bacterial cell-wall biosynthesis remains a well-established and robust target for natural product screening [48]. This mechanism is restricted to prokaryotes and is thus less toxic to mammals. Cell-wall synthesis features remarkable structural and functional complexity, and can thus be impaired by inhibiting a variety of steps, including the biogenesis of dedicated monomers and specific assembly, membrane translocation and extracellular cross-linking, and strengthening of the exoskeletal

Lantibiotics: novel cell-wall inhibitors

Investigation of underexplored microbial niches, poorly screened bacterial taxa and the genomes of well-studied bacteria might yield novel antibiotics, especially if new screening strategies can bypass the time-consuming problem of rediscovering known compounds. Expansion of the chemical and genetic diversity of microbial sources to be screened has recently led to the discovery of novel lantibiotics 51, 52 and engineering of their producer strains to generate a library of variants of known

Retrospective strategy

Examples of rediscovered compounds from natural sources are the cyclic mannopeptimycins and the lipodepsipeptide ramoplanin. These compounds inhibit certain steps of the lipid II cycle in a manner not yet fully explained, probably by arresting the flux of peptidoglycan precursors to the cross-linking transglycosylases and transpeptidases (Figure 2). Mannopeptimycins are a family of glycopeptides first isolated from Streptomyces species in the 1950 s. They inhibit lipid-II-dependent peptidoglycan

Alternative measures: combination therapy, phages and vaccines

Although β-lactams and glycopeptides are still the first and last line of defense, there is a critical need for novel effective therapies against bacterial infections. Ideally, such alternative therapies should put no selective pressure that could lead to resistance in bacteria.

Combination therapy might be another weapon against multi-resistant bacteria (Box 2; Figure 3) [74]. Synergistic activity of glycopeptides (vancomycin or teicoplanin) and β-lactams (e.g. oxacillin) against VRSA has been

Conclusions

Medical care requires new antibiotics owing to the growing prevalence of resistant pathogens in hospital or community-acquired infections. Notwithstanding this need, major pharmaceutical companies have reduced their R&D efforts in the search for new antibiotics. This is attributed to a combination of factors, including commercial considerations regarding the maturity of new drug candidates, strong competition among pharmaceutical companies and the increase in generic antibiotics on the market.

Glossary

Depsipeptides
natural or synthetic compounds having sequences of amino and hydroxy carboxylic acid residues (usually α-amino and α-hydroxy acids) that commonly, but not necessarily, alternate regularly. An example is the l-Lys-d-Ala-d-Lac motif found in the cell-wall building blocks of vancomycin-resistant bacteria. The amide→ester mutation disrupts its hydrogen bonding network with vancomycin, which is key to the antibiotic activity.
Gram-positive bacteria
stained dark blue or violet by Gram

References (83)

  • J.F. Barrett

    Can biotech deliver new antibiotics?

    Curr. Opin. Microbiol.

    (2005)
  • S.S.F. Leung

    Vancomycin analogs: Seeking improved binding of d-Ala-d-Ala and d-Ala-d-Lac peptides by side-chain and backbone modifications

    Bioorg. Med. Chem.

    (2009)
  • S.S.F. Leung

    Vancomycin resistance: modeling backbone variants with D-Ala-D-Ala and D-Ala-D-Lac peptides

    Bioorg. Med. Chem. Lett.

    (2009)
  • F. Castiglione

    Determining the structure and mode of action of microbisporicin, a potent lantibiotic active against multiresistant pathogens

    Chem. Biol.

    (2008)
  • G. Cornaglia et al.

    Forthcoming therapeutic perspectives for infections due to multidrug-resistant Gram-positive pathogens

    Clin. Microbiol. Infect.

    (2009)
  • D. Abbanat

    New agents in development for the treatment of bacterial infections

    Curr. Opin. Pharmacol.

    (2008)
  • R. Shi

    Structure and function of the glycopeptide N-methyltransferase MtfA, a tool for the biosynthesis of modified glycopeptide antibiotics

    Chem. Biol.

    (2009)
  • Y. Zou

    Crystal structures of lipoglycopeptide antibiotic deacetylases: implications for the biosynthesis of A40926 and teicoplanin

    Chem. Biol.

    (2008)
  • A.N. Appleyard

    Dissecting structural and functional diversity of the lantibiotic mersacidin

    Chem. Biol.

    (2009)
  • T. Schneider et al.

    An oldie but a goodie – cell wall biosynthesis as antibiotic target pathway

    Int. J. Med. Microbiol.

    (2010)
  • G. Cottarel et al.

    Combination drugs, an emerging option for antibacterial therapy

    Trends Biotechnol.

    (2007)
  • V. Fischetti

    Bacteriophage lysins as effective antibacterials

    Curr. Opin. Microbiol.

    (2008)
  • M. Kutateladze et al.

    Bacteriophages as potential new therapeutics to replace or supplement antibiotics

    Trends Biotechnol.

    (2010)
  • Y. Nitanai

    Crystal structures of the complexes between vancomycin and cell-wall precursor analogs

    J. Mol. Biol.

    (2009)
  • C. Walsh

    Antibiotics: Actions, Origins, Resistance

    (2003)
  • J. Tramper

    Biocatalytic production of semi-synthetic cephalosporins: process technology and integration

  • A.L. Demain et al.

    The beta-lactam antibiotics: past, present, and future

    Antonie Van Leeuwenhoek

    (1999)
  • A.L. Demain et al.

    Microbial drug discovery: 80 years of progress

    J. Antibiot.

    (2009)
  • B.R. Lyon et al.

    Antimicrobial resistance of Staphylococcus aureus: genetic basis

    Microbiol. Rev.

    (1987)
  • W.C. Gaisford et al.

    Methicillin resistance in Staphylococcus epidermidis

    Eur. J. Biochem.

    (1989)
  • H.F. Chambers

    Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications

    Clin. Microbiol. Rev.

    (1997)
  • M. Holden

    Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • H.F. Chambers et al.

    Waves of resistance: Staphylococcus aureus in the antibiotic era

    Nat. Rev. Microbiol.

    (2009)
  • T. Ito

    Classification of staphylococcal cassette chromosome mec (SCCmec): guidelines for reporting novel SCCmec elements

    Antimicrob. Agents Chemother.

    (2009)
  • S. Tsubakishita

    The origin and molecular evolution of the determinant of methicillin-resistance in staphylococci

    Antimicrob. Agents Chemother.

    (2010)
  • P. Courvalin

    Vancomycin resistance in Gram-positive cocci

    Clin. Infect. Dis.

    (2006)
  • P. Courvalin

    Predictable and unpredictable evolution of antibiotic resistance

    J. Intern. Med.

    (2008)
  • R. Leclercq

    Transferable vancomycin and teicoplanin resistance in Enterococcus faecium

    Antimicrob. Agents Chemother.

    (1989)
  • M. Larkin

    Antibacterial resistance deemed a public-health crisis

    Lancet Infect. Dis.

    (2003)
  • K. Hiramatsu

    Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility

    J. Antimicrob. Chemother.

    (1997)
  • S. Chang

    Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene

    N. Engl. J. Med.

    (2003)
  • Cited by (78)

    • Anti-Bacterial Agents

      2022, Encyclopedia of Infection and Immunity
    View all citing articles on Scopus
    View full text