Antibiotics that bind to the 50S ribosomal subunit.
Chloramphenicol subclass. This subclass includes chloramphenicol (CAM), lincomycin, and clindamycin, which are bacteriostatic. CAM is active against
gram-positive and gram-negative bacteria, but lincomycin and clindamycin have a restricted spectrum of activity. Resistance
to all three is common.
CAM's effect on bacteria stems from the inhibition of bacterial protein synthesis (56). The molecular target for CAM is the
peptidyl transferase (PTF) enzyme that links amino acids in the growing peptide chain (57). The antibiotic halts the process
of chain elongation, thus stopping bacterial growth (58, 59). The process is completely reversible, and CAM is fundamentally
a bacteriostatic agent. The binding of CAM to the 50S subunit of 70S ribosomes is highly specific.
Many bacteria are resistant to CAM. The main mechanisms for resistance are covalent modification of the antibiotic by the
enzyme chloramphenicol acetyl transferase or CAT (so that the antibiotic no longer binds to ribosomes) and efflux pumps (60).
Macrolides. Macrolides bind specifically to the PTF site. This group includes erythromycin (ERY), azithromycin, clarithromycin, and dirithromycin.
ERY is the best known agent of this group. It is a bacteriostatic agent that is only active against gram-positive bacteria,
Mycoplasma spp. and Legionella spp. Resistance is common. Depending on drug concentration, bacterial species, and phase of growth, ERY may act in different ways.
The main modes of action for ERY, and macrolides in general, are the following:
- Large macrolides bind near the PTF center and block the nascent peptide from emerging from the ribosome, thus inhibiting the
elongation of most peptides and destabilizing the ribosome–peptidyl–tRNA complex.
- Small macrolides partially block the ribosome channel and inhibit peptide elongation depending on the conformation of the
- The nascent peptide chain becomes stuck inside the ribosome, thus inhibiting protein synthesis.
- The ribosome-peptidyl-tRNA complex that inactivates the ribosome is stabilized (61).
Bacteria are resistant to macrolides in at least three ways. Methylation can modify the target site and prevent the antibiotic
from binding to its ribosomal target. Efflux pumps and drug inactivation also provide resistance (62, 63).
Antibiotics that interfere with elongation factors.
Fusidic acid (FAc) is a steroid-like bacteriostatic antibiotic (64). It inhibits the translocation step in protein synthesis
by binding to elongation factor G or EF-G (65, 66). Resistance results from the following two causes:
- Production of an altered EF-G with decreased FAc affinity (67)
- Extracellular enzymes that inactivate FAc (68).
Inhibitors of nucleic-acid synthesis and function. Inhibitors of RNA synthesis and function. These antimicrobials bind to DNA-dependent RNA polymerase (DDRP) and inhibit the initiation of RNA synthesis. They have a
wide spectrum of activity, but are most commonly used to treat tuberculosis. These agents are bactericidal, but resistance
is common. This group includes rifampin, rifampicin, rifabutin, and rifapentine.
The most popular agent in this group is rifampin, which binds to the RNA polymerase and inhibits transcription (69). Mutations
in the DDRP gene are associated with rifampin resistance (70). Isolates resistant to rifampin have reduce susceptibilities
to rifapentine, rifabutin, and other rifamycins (71). Hence, cross-resistance among the rifamycins is common.
Inhibitors of DNA synthesis and function. Quinolones are bactericidal. The first quinolone, nalidixic acid, was introduced in 1962 (72). Since then, modifications
to the structure of nalidixic acid have resulted in second-, third-, and fourth-generation fluoroquinolones that have improved
activity against gram-positive, gram-negative, and anaerobic bacteria (73–75).
Target sites of quinolones are DNA gyrase (topoisomerase II) and topoisomerase IV or Top IV (76–81). DNA topoisomerases are
enzymes that control and modify the topological states of DNA in cells. DNA gyrase catalyzes the negative supercoiling of
prokaryotic DNA (82, 83). This supercoiling is essential for initiating and continuing DNA synthesis and for the transcription
of mRNA from genes. Top IV, unlike DNA gyrase, cannot catalyze the supercoiling of DNA; it can only catalyze its relaxation.
Top IV is responsible for cell division after DNA replication (84, 85).