Antibiotics; Inhibitors of Protein and DNA Synthesis LECTURE 11: Microbiology and Virology; 3 Credit hours Atta-ur-Rahman School of Applied Biosciences (ASAB) National University of Sciences and Technology (NUST)

Inhibitors of Protein Synthesis They are mostly bacteriostatic. 1.Antimicrobials that bind to the 30s Ribosomal Subunit 2.Antimicrobials that bind to the 50s Ribosomal Subunit 3.Antimicrobials that interfere with Elongation Factors The selectivity of these agents is a result of differences in the prokaryotic 70S ribosome and the 80S eukaryotic ribosome. Since mitochondrial ribosomes are similar to prokaryotic ribosomes, these anti-metabolites can have some toxicity.

1- Aminoglycosides The aminoglycosides (streptomycin, neomycin, netilmicin, tobramycin, gentamicin, amikacin, etc.) bind irreversibly to the 16S rRNA in the 30S subunit of bacterial ribosomes. It has been proposed that some aminoglycosides prevent the transfer of the peptidyl tRNA from the A- site to the P-site, thus preventing the elongation of the polypeptide chain. Aminoglycosides Interfering with the Translocation of tRNA from the A-site to the P- site

2- Tetracycline The tetracyclines (tetracycline, doxycycline, minocycline, etc.) block bacterial translation by binding reversibly to the 16S rRNA in the 30S subunit and distorting it in such a way that the anticodons of the charged tRNAs cannot align properly with the codons of the mRNA.

3- Chloramphenicol, lincomycin, clindamycin These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. Chloramphenicol is toxic (bone marrow suppression) but it is used in the treatment of bacterial meningitis.

4- Macrolides Macrolides (bacteriostatic ) - Erythromycin (also azithromycin, clarithromycin) The macrolides inhibit translocation of the peptidyl tRNA from the A to the P site on the ribosome by binding to the 50S ribosomal 23S RNA.

5- Fusidic acid Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex. The elongation factor responsible for moving peptidyl-tRNA from the ribosomal A- site to the P-site during translation. It makes use of a ribosomal GTPase to rotate the small (30S) ribosomal subunit with respect to the large (50S) subunit.

6- Inhibitors Of RNA Synthesis Rifampin, rifamycin, rifampicin These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of RNA synthesis.

7- Inhibitors of DNA Synthesis Quinolones - nalidixic acid, ciprofloxacin, oxolinic acid (bactericidal). These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis.