Figure 11-3 Structure of vancomycin, a non-beta-lactam antibiotic that inhibits cell wall synthesis. (Modified from Salyers AA, Whitt DD, editors: Bacterial pathogenesis: a molecular approach, Washington, DC, 1994, ASM Press.)
reach their cell wall precursor targets. Therefore, this agent is usually ineffective against gram-negative bacteria.
Several other cell wall-active antibiotics have been discovered and developed over the years, but toxicity to the human host has prevented their widespread clinical use. One example is bacitracin, which inhibits the recycling of certain metabolites required for maintaining peptidoglycan synthesis. Because of potential toxicity, bacitracin is usually only used as a topical antibacterial agent and internal consumption is generally avoided.
Daptomycin, a lipopeptide agent that has recently been approved for clinical use is the most recent agent developed that exerts its antimicrobial effect by binding and disrupting the cell membrane of grampositive bacteria. Although the exact mechanism of action is not fully understood, daptomycin has potent activity against gram-positive cocci, including those resistant to other agents such as beta-lactams and glyco-peptides (e.g., methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci [VRE], and vancomycin-resistant S. aureus [VRSA]). Because of the molecule's size, daptomycin is unable to penetrate the outer membrane of gram-negative bacilli and thus is ineffective against that group of organisms.
Polymyxins (polymyxin B and colistin) are older agents that disrupt bacterial cell membranes. This disruption results in leakage of macromolecules and ions essential for cell survival. Because their effectiveness varies with the molecular makeup of the bacterial cell membrane, polymyxins are not equally effective against all bacteria. Most notably they are more active against gram-negative bacteria, while activity against grampositive bacteria tends to be poor. Furthermore, human host cells also contain membranes so that toxicity risks do exist with the use of polymyxins. Although toxic, the polymyxins are often the antimicrobial agents of last resort when gram-negative bacilli (e.g. Pseudomonas aeruginosa, Acmetobacter spp.) resistant to all other available agents are encountered.
Several classes of antibiotics target bacterial protein synthesis and severely disrupt cellular metabolism. Antibiotic classes that act by inhibiting protein synthesis include aminoglycosides, macrolide-lincosamide-streptogramins (MLS group), ketolides (e.g„ telithro-mycin) chloramphenicol, tetracyclines, glycylglycines (e.g., tigecydine), and oxazolidinones (e.g., linezolid). Although these antibiotics are generally categorized as protein synthesis inhibitors, the specific mechanisms by which they inhibit protein synthesis differ significantly.
Aminoglycosides. Aminoglycosides inhibit bacterial protein synthesis by binding to protein receptors on the organism's 30S ribosomal subunit. This process interrupts several steps, including initial formation of the protein synthesis complex, accurate reading of the mRNA code, and formation of the ribosomal-mRNA complex. The structure of a commonly used aminoglycoside, gentamidn, is given in Figure 11-4. Other available aminoglycosides include tobramycin, amikacin, netilmicin, streptomycin, and kanamycin. The spectrum of activity of aminoglycosides includes a wide variety of gram-negative and gram-positive bacteria. Aminoglycosides are often used in combination with cell wall-active antibiotics, such as beta-lactams or vancomycin, to achieve more rapid killing of certain bacteria. Anaerobic bacteria cannot take up these agents intracellularly so they are usually not inhibited by aminoglycosides.
Macrolide-Lincosamide-Streptogramin (MLS) Group.
The most common antibiotics in the MLS group include the macrolides, such as erythromycin, azithromycin, and clarithromycin, and clindamycin (a lincosamide). Protein synthesis is inhibited by drug binding to receptors on the bacterial 50S ribosomal subunit and subsequent disruption of the growing peptide chain. Primarily because of uptake difficulties associated with gram-
Figure 11-4 Structure of the commonly used aminoglycoside gentamicin. Potential sites of modification by adenylylating, phosphorylating, and acetylating enzymes produced by bacteria a: highlighted. (Modified from Salyers AA, Whitt DD, editors: Bacterial pathogenesis: a molecular approach, Washington, DC, 1994, ASM Press.)
negative outer membranes, the macrolides and clindamycin generally are not effective against most genera of gram-negative bacteria. However, they are effective against gram-positive bacteria. Newer agents include quinupristin/dalfopristin, which is a dual streptogramin that targets two sites on the 50S ribosomal subunit.
Inhibitors of DNA and RNA Synthesis
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