Factors influencing the antibacterial action of -lactam antibiotics

Abstract

Effective antibacterial agents act at one or more targets in the bacterial cell, reach those targets in sufficient amounts, and avoid inactivation by substances produced by the cell. β-Lactam antibiotics inhibit biosynthesis of the peptidoglycan component of bacterial cell walls by inhibiting enzymic activity (binding proteins), probably transpeptidases and carboxypeptidases. β-Lactam antibiotics seem to have easy access to targets in most Gram-positive bacteria, but have difficulty penetrating Gram-negative cells. One source of the differences in sensitivity of bacteria to β-lactam antibiotics is probably due to variations in the components of the peptidoglycan biosynthetic system. Clinical resistance to β-lactam antibiotics is usually attributable to a β-lactamase and, in Gram-negative bacteria, to a denial of access of the antibiotic to the target, probably by the outer membrane of the bacterial envelope. Antibiotics may pass across the bacterial membrane through protein molecules (‘studs’) that link opposite surfaces of the membrane. Penetration of β-lactam antibiotics cannot yet be measured directly. Although Gram-negative bacteria produce less β-lactamase/unit than do Gram-positive bacteria, the enzyme is more advantageously located in the former. To be effective in Gram-negative organisms, a β-lactam antibiotic must be insensitive to a wide range of β-lactamases, able to penetrate the outer membrane of the bacterial envelope, and possess activity against peptidoglycan biosynthesis.