Bacterial cells differ from mammalian cells due to highly developed cell walls outside the cytoplasmic membranes that provide structural integrity and shape to the cell. Bacteria live in dilute aqueous environments, which causes an intracellular pressure equivalent of 10-25 atm. Without the structural support of the cell wall, the cell is susceptible to lysis and osmotic rupture due to osmotic rupture due to turgor pressure.
Figure 1: Comparison between gram-positive bacterial cell walls and gram-negative bacterial cell walls.
Structural differences in the bacterial cell walls cause bacteria to be subcategorized into gram-positive and gram-negative. Gram-positive cell walls (e.g. Bacillus subtilis, Streptococcus …show more content…
Fleming had been culturing colonies of Staphylococcus when one of the plates, untreated by Lysol, had been contaminated by Penicillium notatum. Fleming observed that the growth of staphylococci had been inhibited in the area immediately surrounding the mold, suggesting that the mold secreted an antibacterial compound (Figure 3). The compound was isolated in 1939 through alumina column chromatography by Sir Howard Florey and Ernst Chain.
In 1941, Florey and Chain investigated the clinical use of penicillin to combat bacterial infection in humans. Albert Alexander was the first patient to be treated with penicillin for a Streptococci and Staphylococci infection in his mouth. Following his first dose of penicillin, he began seeing improvement in his condition, although there was not a large enough supply of penicillin for Alexander to fully recover due to production difficulties, and he ultimately …show more content…
Figure 2: Penicillin
Mechanism of Action of β-lactam Antibiotics β-lactam antibiotics function by inhibiting peptidoglycan biosynthesis. In 1965, Donald Tipper and Jack Strominger determined that that penicillin is a substrate or transition state analog of the acyl-D-Ala-D-Ala of uncross-linked peptidoglycan. The inhibition of the DD-transpeptidase occurs due to the nucleophilic attack of the carbonyl on the β-lactam ring by the serine hydroxyl group in the enzyme active site, thus producing a stable acyl-enzyme complex. The tetrahedral structure is then broken at the amide bond, allowing the nitrogen within the ring to be reduced.
Scheme 2: β-lactam antibiotic mechanism with DD-transpeptidase STAND IN.
Therefore, the covalent bond between the β-lactam antibiotic and the DD-transpeptidase prevents the cross-linking of the NAM subunits, thus the peptidoglycan layer of the bacterial cell wall cannot be synthesized. Without the cell wall, the bacterial cell is vulnerable to turgor pressure and lysis, eventually leading to cell