Protein Synthesis Inhibitors

Many antibiotics inhibit protein synthesis by binding with the bacterial ribosome and other components of protein synthesis. Because these drugs discriminate between bacterial and eukaryotic ribosomes, their therapeutic index is fairly high but not as high as that of cell wall synthesis inhibitors. Several different steps in protein synthesis can be affected by drugs in this category.

Aminoglycosides

Although considerable variation in structure occurs among several important aminoglycoside antibiotics, all contain a cyclohexane ring and amino sugars.
Streptomycin, kanamycin, neomycin, and tobramycin are synthesized by different species of the bacterial genus Streptomyces, whereas gentamicin comes from a related genus, Micromonospora purpurea. Streptomycin’s usefulness has decreased greatly due to widespread drug resistance, but it may still be effective when other aminoglycosides should not be used (e.g., due to interactions with other drugs).

Gentamicin is used to treat Gram-negative Proteus, Escherichia, Klebsiella, and Serratia infections.

Aminoglycosides can be quite toxic, however, and can cause hearing and renal damage, loss of balance, nausea, and allergic reactions. Even when not genetically resistant to antibiotics, bacteria can resist the effects of antibiotics by severely slowing their metabolism, minimizing nutrient uptake and thus antibiotic uptake. These “persister” cells can survive freely and hidden in biofilms.

Aminoglycosides bind to the 30S (small) ribosomal subunit to interfere with protein synthesis. These antibiotics are bactericidal and tend to be most effective against Gram-negative pathogens. It is thought that by binding to bacterial ribosomes, aminoglycosides allow an incorrect amino acid to be brought to the ribosome by transfer RNA (tRNA). This yields a protein with a different amino acid sequence than the normal protein. Any abnormal proteins bound for secretion from the cell are inserted into the plasma membrane, where they induce changes in metabolic pathways that result in hydroxyl radical formation. Thus aminoglycosides deliver a two-fold punch: protein synthesis is altered and oxygen radical production increases. It is therefore not surprising that these drugs are bacteriocidal not bacteriostatic.

Tetracyclines

The tetracyclines are a family of antibiotics with a common four-ring structure to which a variety of side chains are attached. Oxytetracycline and chlortetracycline are produced naturally by Streptomyces species, whereas other tetracyclines are semisynthetic. These antibiotics are similar to the aminoglycosides in that they can combine with the 30S subunit of the ribosome, inhibiting protein synthesis. Their action is only bacteriostatic, though. Tetracyclines are broad-spectrum antibiotics that are active against most bacteria, including the intracellular pathogens rickettsias, chlamydiae, and mycoplasmas.

Sulfonamides or Sulfa Drugs Sulfonamides

, or sulfa drugs, are structurally related to sulfanilamide, an analogue of p-aminobenzoic acid, or PABA . PABA is an important component (cofactor) of many enzymes and is needed for folic acid (folate) synthesis. Folic acid is a precursor of purines and pyrimidines, the bases used in the construction of DNA, RNA, and other important cell constituents (e.g., ATP). When sulfanilamide or another sulfonamide enters a bacterial cell, it competes with PABA for the active site of an enzyme involved in folic acid synthesis, causing a decline in folate concentration. The resulting inhibition of purine and pyrimidine synthesis leads to cessation of protein synthesis and DNA replication. Sulfonamides are selectively toxic for many bacteria and protozoa because these microbes manufacture their own folate and cannot effectively take up this cofactor, whereas humans do not synthesize folate; instead, we must obtain it in our diet. Sulfonamides thus have a high therapeutic index. However, the increasing resistance of many bacteria to sulfa drugs limits their effectiveness.

Nucleic Acid Synthesis Inhibition

The antibacterial drugs that inhibit nucleic acid synthesis function by inhibiting (1) DNA polymerase and topoisomerases or (2) RNA polymerase, to block replication or transcription, respectively. These drugs are not as selectively toxic as other antibiotics because bacteria and eukaryotes do not differ greatly with respect to nucleic acid synthesis. The most commonly used drugs in this category are the quinolones.

Quinolones

The quinolones are synthetic drugs that contain the 4-quinolone ring. They are increasingly used to treat a wide variety of infections. The first quinolone, nalidixic acid , was synthesized in 1962. Since that time, generations of fluoroquinolones have been produced. Three of these-ciprofloxacin, norfloxacin, and ofloxacin-are currently used in the United States, and more fluoroquinolones are being synthesized and tested.

Quinolones act by inhibiting the bacterial topoisomerases DNA gyrase and topoisomerase II. DNA gyrase introduces negative twist in DNA and helps separate its strands. Inhibition of DNA gyrase disrupts DNA replication and repair, bacterial chromosome separation during division, and other processes involving DNA. Fluoroquinolones also inhibit topoisomerase II,

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