PartII Resistance Among the first antibiotics used on a large scale was penicill
ID: 53143 • Letter: P
Question
PartII Resistance Among the first antibiotics used on a large scale was penicillin, which was discovered in 1929 by Alexander Fleming. It was finally isolated and synthesized in large quantities in 1943. Penicillin works by interfering with the bacterial cell wall synthesis. Without a cell wall, the bacterial cells cannot maintain their shape in changing asmotic conditions. This puts significant selective pressure on the microbes to evolve, as they cannot survive the osmotic stress. Any microbe that can resist these drugs will survive and reproduce more, making the population of microbes antibiotic resistant. The specific mechanism of penicillin is the prevention of cell wall synthesis by the -lactam ring of the antibiotic (Fig 3), which binds and inhibits an enzyme required by the bacterium in this process. The enzyme is called penicillin-binding protein (PBP), even though it is an enzyme involved in cell wall synthesis. Normally enzymes have names that indicate what they do and end in the suffix -ase, like lactase, the enzyme that breaks down lactose. igure 4 is a representation of PBP and its active site. NH 3The Figure 3. The -lactann ring coothe penicillin family of antibiotics. Active site Figure 4 PBP (penicillin-binding protein) active site is a groove allowing fomation of cross links in the bacterial cell wall. Bacterial cell walls are layered structures, where each layer is made of peptidoglycan, a sugar and protein polymer. Each layer is cross-linked to the next, strengthening the wall and allowing the cell to resist osmotic pressure. The way the enzyme PBP works is to form those crss-bridges by joining strings of amino acids together in the active site, which is a groove in the protein (Fig. 5) Cross-bridge PBP Peptidoglycan ayers Amino acids Figure 5 Cross-link formation in bacterial cell walls by PBP (penicillin-binding protein).Explanation / Answer
1. Fig.7 is showing:- PBP binds NAM and NAG linkages of peptidoglycan to join them together; and make the cell wall a strong structure. If penicillin attacks the bacterial cell, it's beta lactam ring binds first with the PBP protein. This complex then binds to one NAM-NAG chain, so these chains are unable to attach to attach to each other, because the other side of the PBP protein has been occupied by the beta lactam ring. Finally the chains are unable to attach to each other, making the cell wall a weak structure which will disrupt after some time.
Fig.8 is showing:- If vancomycin attacks the bacterial cell, it binds with one NAM-NAG chains directly, so these chains are unable to attach to each other, making the cell wall a weak structure which will disrupt after some time.
2. beta lactam antibiotics cannot bind to cell wall directly. They will first bind PBP, and make a complex. This complex is going to bind to the peptidoglycan chain.
Vancomycin directly binds to the peptidoglycan chain.
3. In some bacteria , beta lactamases are present, which disrupt the beta lactam ring and provide resistance against beta lactam containing antibiotics. Altering the permeability of bacterial cell wall is another way of achieving resistance.
4. Vancomycin forms complex with cell wall of bacteria. It binds to C- terminus of pentapeptide made up of Alanine in the cell wall. The precursor of this pentapeptide is formed inside the cell cytoplasm. If the permeability of cell wall is altered, dis-allowing the D-alanine pentapeptide to come out of the cell, then vancomycin will not get any site for binding. Thus, the bacteria will achieve resistance to vancomycin.