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.

Inhibitors of Cell Membrane Function

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.

Inhibitors of Protein Synthesis

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-

  • Polenliai sites for acetylation
  • Potential sites for adenylylation or phosphorylation

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.

  1. This group of compounds is made up of chemical derivatives related to erythromycin and other macrolides. As such, they too act by binding to the 50S ribosomal subunit and inhibiting protein synthesis. The key difference between the only currently available ketolide (i.e„ telithromydn) and macrolides is that this ketolide maintains activity against most macrolide-resistant gram-positive organisms and does not induce a common macrolide resistance mechanism (i.e., the MLSb methylase) that alters the ribosomal target.
  2. Oxazolidinones, currently represented by linezolid, are a relativdy new dass of antibacterial agent available for clinical use. Linezolid is a synthetic agent that inhibits protein synthesis through a unique mechanism. Therefore, linezolid is not expected to be affected by resistance mechanisms that affect other drug dasses.
  3. Chloramphenicol inhibits the addition of new amino adds to the growing peptide chain by binding to the SOS ribosomal subunit. This antibiotic is highly active against a wide variety of gramnegative and gram-positive bacteria; however, its use has dwindled because of serious toxidty assodated with it and the development of many other effective and safer agents, mostly of the beta-lactam class.
  4. Tetracyclines inhibit protein synthesis by binding to the 30S ribosomal subunit so that incoming tRNA-amino add complexes cannot bind to the ribosome, thus halting peptide chain elongation. Tetracyclines have a broad spectrum of activity that indudes gram-negative bacteria, gram-positive bacteria, and several intracellular bacterial pathogens such as chlamydia, rickettsia, and rickettsia-like organisms. Similar to chloramphenicol, the development of several effective beta-lactams has caused a marked decrease in the use of these agents.
  5. These agents are synthetic derivatives related to the tetracycline class and tigecycline is the first agent of this dass to be approved for clinical use. Similar to the tetracyclines, tigecycline inhibits protein synthesis by binding to the 30S ribosomal subunit. However, tigecycline has the advantage of being refractory to the most common tetracycline resistance mechanisms expressed by gram-negative and gram-positive bacteria.

Inhibitors of DNA and RNA Synthesis

The primary antimicrobial agents that target DNA metabolism are the fluoroquinolones and metronidazole.

  1. Fluoroquinolones, also often simply referred to as quinolones, are derivatives of nalidixic add, an older antibacterial agent. The structures of two quinolones, dprofloxadn and ofloxacin, are shown in Figure 11-5. These agents bind to and interfere with DNA gyrase enzymes involved in the regulation of bacterial DNA supercoiling, a process that is essential for DNA replication and transcription. The fluoroquinolones are potent bacteriddal agents, and they have a broad spectrum of activity that indudes gram-negative and gram-positive bacteria. However, the spectrum of activity can vary with each individual quinolone agent
  2. The exact mechanism for metronidazole's antibacterial activity is uncertain, but it is believed to involve direct interactions between the activated drug and DNA that results in breakage of DNA strands. Activation of metronidazole requires reduction under conditions of low redox potential such as that found in anaerobic environments. Therefore, this agent is most potent against anaerobic bacteria, notably those that are gram-negative.

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Bacterial Vaginosis Facts

Bacterial Vaginosis Facts

This fact sheet is designed to provide you with information on Bacterial Vaginosis. Bacterial vaginosis is an abnormal vaginal condition that is characterized by vaginal discharge and results from an overgrowth of atypical bacteria in the vagina.

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