Antimicrobial Drugs: Cell Wall as Drug Target PDF

28.10 Antimicrobial Drugs: The cell wall as a drug target Most of the over 100,000 metric tons of antibiotics used worldwide each year are -lactam antibiotics. (Figure 28.28 A, B) The -lactam ring is found in penicillins and cephalosporins. (Figure 28.29) – These drugs inh...

28.10 Antimicrobial Drugs: The cell wall as a drug target Most of the over 100,000 metric tons of antibiotics used worldwide each year are -lactam antibiotics. (Figure 28.28 A, B) The -lactam ring is found in penicillins and cephalosporins. (Figure 28.29) – These drugs inhibit cell wall synthesis.  Cell wall synthesis and targeting The major structural component of most bacterial cell walls is the peptidoglycan layer. The building of the chains and cross-links is catalyzed by specific enzymes (e.g., transpeptidases, transglycosylases, carboxypeptidases) that are members of a large family of serine proteases. These regulatory enzymes are also called penicillin- → - binding proteins (PBPs) - t help make cellwanll  Penicillin, the first antibiotic 1928: Alexander Fleming noticed that a mould (Penicillium notatum) produced a compound that inhibits bacterial growth. 1940: Florey and Chain showed that an injection of extract cured infections in mice and later in humans. 1945: Fleming, Florey and Chain were awarded a Nobel Prize for Medicine.  Cephalosporin Penicillins Core structure of penicillins (top) and cephalosporins (bottom). -lactam ring in red. Different in -lactamase resistance and pharmacokinetic properties Figure 28.29  Resistant to -lactam antibiotics 1. Bacteria can become resistant to -lactam antibiotics by three general mechanisms: 1) Prevention of the interaction between the antibiotic and the target PBP; 2) Modification of the binding of the antibiotic to the PBP; 3) Hydrolysis of the antibiotic by bacterial enzymes, -lactamases. Resistance can also be acquired by modification of the -lactam antibiotic binding to the PBP. This can be mediated by: 1. An overproduction of PBP (a rare occurrence); 2. Acquisition of a new PBP (e.g., methicillin resistance in Staphylococcus aureus [MRSA]); 3. Modification of an existing PBP gene through recombination (e.g., penicillin resistance in Streptococcus pneumoniae) or a point mutation (penicillin resistance in Enterococcus faecium) – basically enhancing the functions of PBP.. ω 예  Other cell wall inhibitors Glycopeptide - Vancomycin ∅ Vancomycin, originally obtained from Streptomyces orientalis, is a complex glycopeptide that disrupts cell wall peptidoglycan synthesis in growing gram-positive bacteria. Vancomycin is considered as the most potent antibiotic and the last defense line to superbugs. Can be used for antibiotic resistant C. diff. Vancomycin must be given intravenously for systemic therapy, since it is not absorbed from the intestine. Vancomycin interacts with the D-alanine-D-alanine termini of the pentapeptide side chains, which interferes sterically with the formation of the bridges between the peptidoglycan chains. In addition, some organisms are intrinsically resistant to vancomycin (e.g. Lactobacillus). Some species of Enterococci have acquired resistance to vancomycin. Protein synthesis as a drug target Most of the antibiotics targeting protein synthesis will target translation by binding to the bacterial ribosome. Bacterial ribosomes are slightly different than eukaryotic ribosomes, giving selective toxicity. Examples of antibiotics that target protein synthesis include: aminoglycosides, tetracyclines, and macrolide antibiotics.  Ribosome and antibiotics https://www.slideshare.net/jeevanjacob11/antibiotics-targeting-the-50-s-ribosomal-subunit