Kanamycin and tobramycin have been reported to bindto the ribosomal 30S subunit and to prevent it from joining to the 50Ssubunitduring protein synthesis. They may have a bactericidal effect becausethisleads to cytoplasmic accumulation of dissociated 30S subunits, which isapparently lethal to the cells.
Penicillins exert their bactericidal activity primarily by inhibiting bacterial cell wall synthesis. Though the exact mechanism of action is not fully elucidated, it appears that penicillins bind to penicillin-binding proteins (PBPs), which are enzymes (transpeptidases, carboxypeptidases, and endopeptidases) that play an important role in the formation and maintenance of the cell wall structure. The cell wall is made up of peptidoglycan, or murein sacculus, which is a polymeric component consisting of long polysaccharide chains of N-acetylglucosamine and N-acetylmuramic acid cross-linked by shorter peptide chains. The formation of peptidoglycan can be divided into three stages, including precursor formation in the cytoplasm, linkage of precursor products into a long polymer, and finally cross-linking by transpeptidation. It is the final transpeptidation process that is inhibited by penicillins by acting as a structural analog of acyl-D-alanyl-D-alanine (the substrate of the enzyme) and acylating the transpeptidase enzyme. The peptidoglycan structure, and therefore the cell wall structure, is weakened, leading to cell death (, , ). Other mechanisms of cell death are also possible. Binding to PBPs 1A, 1B, 2, and 3 results in a bactericidal effect (), however binding to PBPs 4, 5, and 6 is not lethal. Also, there are differences in PBPs between gram-positive and gram-negative bacteria and there are differences in affinity between penicillin compounds to various PBPs. These differences can affect spectrum of activity.
Inhibition of protein synthesis 3
The agents in this group are also known as the antistaphylococcal penicillins. The addition of an isoxazolyl side chain to the penicillin compound protects the beta-lactam ring from acid hydrolysis by penicillinases produced by Staphylococcus sp. (). Methicillin, the first agent synthesized in this group, is rarely used currently due to a higher incidence of occurrence of interstitial nephritis and is no longer commercially available in the United States. Nafcillin and oxacillin are the agents commonly used parenterally, while dicloxacillin is available for oral use. These agents have activity against Staphylococcus sp (including penicillinase-producing strains). Strains of methicillin-resistant Staphylococcus aureus(MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) exist and can be the prevalent Staphylococcal organism in certain areas, such as certain hospitals or wards within the hospital. These organisms are not sensitive to the penicillinase-resistant penicillins.