Trends in Biotechnology
Reviewβ-Lactam and glycopeptide antibiotics: first and last line of defense?
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
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