Beta-Lactam Antibiotics.ppt

Production All commercially available β-lactams are initially produced through the fermentation of bacteria. Bacteria assemble the penicillin molecule from L-AAA, L-valine, and L-cysteine in three steps using ACV synthase, IPN synthase, and acyltransferase. Modern recombinant genetic techniques have allowed the over expression of the genes which code for these three enzymes, allowing much greater yields of penicillin than in the past. Penicillin Biosynthetic Pathway o Semi-Synthetic Penicillins The acyl side chain of the penicillin molecule can be cleaved using enzyme or chemical methods to produce 6-APA, which can further be used to produce semi-synthetic penicillins or cephalosporins 75% of the penicillin produced is modified in this manner. Penicillins- Antistaphylococcal Penicillins which have bulky side groups can block the β-Lactamases which hydrolyze the lactam ring. Penicillins- Antistaphylococcal These lactamases are prevalent in S. aureus and S. epidermidis, and render them resistant to Penicillin G and V. This necessitated the development of semi-synthetic penicillins through rational drug design. Methicillin was the first penicillin developed with this type of modification, and since then all bacteria which are resistant to any type of penicillin are designated as methicillin resistant. (MRSA- methicillin-resistant S. aureus) Penicillins- Antistaphylococcal Methicillin is acid sensitive and has been improved upon by adding electron withdrawing groups, as was done in penicillin V, resulting in drugs such as oxacillin and nafcillin. Due to the bulky side group, all of the antistaphylococcal drugs have difficulty penetrating the cell membrane and are less effective than other penicillins. Penicillins- Aminopenicillins In order to increase the range of activity, the penicillin has been modified to have more hydrophilic groups, allowing the drug to penetrate into Gram (-) bacteria via the porins. Ampicillin R=Ph Amoxicillin R= Ph-OH Penicilli