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Designing New β-Lactams: Implications from Their Targets, Resistance Factors and Synthesizing Enzymes

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Penicillins and cephalosporins are β-lactam antibiotics widely used to treat bacterial infectious diseases. They mainly target the cell wall biosynthesis pathway to inhibit bacterial growth. The targets, known as penicillin-binding proteins, are enzymes involved in the polymerization of glycan chains, cross-linking them during bacterial cell wall formation. However, the dispensation of these antibiotics has been concomitant with increasing incidence of resistance to them. Reportedly, this is due to the evolvement of two resistance mechanisms in the bacterial pathogens. One is the production of β-lactamases that cleave the β-lactam rings of penicillin and cephalosporin antibiotics, rendering them ineffective against the pathogens. Another is the modification of the targets, resulting in their inability to bind β-lactam antibiotics. Nevertheless, β-lactam antibiotics remain clinically relevant due to their high target specificity in bacteria and low toxicity to humans. Thus, to overcome the continuing emergence of resistance in pathogens, more efficacious β- lactams have to be developed and cephalosporins are often preferred over penicillins due to two alkyl sites in the cephalosporin core structure amenable for modification. Transformed β-lactams are expected to have improved antimicrobial spectra and pharmacokinetics. This is illustrated by the development of two cephalosporins, namely ceftobiprole and ceftaroline, which have shown good antimicrobial activities and are currently undergoing clinical trials. This review will discuss computer-aided studies of three enzymes closely related to cephalosporins: (1) its synthesizing enzyme, deacetoxycephalosporin C synthase, (2) its targets, the penicillin-binding proteins, and (3) its degrading enzyme, the β-lactamases, and their implications in the development of new cephalosporins.

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Keywords: 2-(N-morpholino)-ethanesulfonic acid, barium ion; Acinetobacter baumannii; Bacillus licheniformis; Bacillus subtilis; Biapenem, zinc ion; Boronic acid inhibitor; CMV; CTX-M-14; CTX-M-27; CTX-M-9; Cefotaxime, 1,2-ethanediol, chloride ion, zinc ion; Cefotaxime, sulphate ion; Chloride ion; Citrobacter sedlakii; Enterobacter cloacae; Escherichia coli; FMZ; Faropenem; Flomox (cefapeme pivoxil hydrochloride); Fluoribacter gormanii; Glycerol; Glycerol, sulphate ion; HXDXnH; Haemophilus influenzae; K213; KTG motif; Klebsiella pneumoniae; L-aminoadipic acid; L-cysteine; L-valine; Lactam Biosynthetic Pathway; Lactivicin, chloride ion, sulphate ion; Laminoadipyl-L-cysteinyl-D-valine; Mercaptoethanol; Mimetic peptide cephalosporin; Mimetic peptide penicillin; Moenomycin; Neisseria gonorrhoeae; Nickel ion; PBP1a; PBP1b; PBP2; PBP2b; PBP2x; PBP4; PBP4a; PBP5; PBP6; PER-1; PSE-4; Pseudomonas aeruginosa; S110; SHV-1; SHV-2; SXN motif; Serratia marcescens; Staphylococcus aureus; Streptococcus pneumoniae; Tebipenem, zinc ion; Zinc ion; azlocillin; cephalosporin; dacA; dacB; dacC; deacetoxycephalosporin C (DAOC); deacetoxycephalosporin C synthase; ftsI; isopenicillin N synthase (IPNS); mecA; mezlocillin; non-lactamase-producing staphylococci; pbp1b; pbp2b; pbpA; penicillin; penicillin-binding proteins; piperacillin; ponB; pvpx; sodium dodecyl sulphate-polyacrylamide gel electrophoresis; tripeptide; β-lactam; β-lactamases

Document Type: Research Article

Publication date: March 1, 2011

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  • Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design. Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, etc., providing excellent rationales for drug development.
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