14.3 Mechanisms of antibacterial drugs  (Page 3/13)

Trimethoprim is a synthetic antimicrobial compound that serves as an antimetabolite within the same folic acid synthesis pathway as sulfonamides. However, trimethoprim is a structural analogue of dihydrofolic acid and inhibits a later step in the metabolic pathway ( [link] ). Trimethoprim is used in combination with the sulfa drug sulfamethoxazole to treat urinary tract infection s, ear infection s, and bronchitis . As discussed, the combination of trimethoprim and sulfamethoxazole is an example of antibacterial synergy. When used alone, each antimetabolite only decreases production of folic acid to a level where bacteriostatic inhibition of growth occurs. However, when used in combination, inhibition of both steps in the metabolic pathway decreases folic acid synthesis to a level that is lethal to the bacterial cell. Because of the importance of folic acid during fetal development, sulfa drugs and trimethoprim use should be carefully considered during early pregnancy.

The drug isoniazid is an antimetabolite with specific toxicity for mycobacteria and has long been used in combination with rifampin or streptomycin in the treatment of tuberculosis . It is administered as a prodrug, requiring activation through the action of an intracellular bacterial peroxidase enzyme, forming isoniazid-nicotinamide adenine dinucleotide (NAD) and isoniazid-nicotinamide adenine dinucleotide phosphate (NADP), ultimately preventing the synthesis of mycolic acid, which is essential for mycobacterial cell walls. Possible side effects of isoniazid use include hepatotoxicity , neurotoxicity , and hematologic toxicity ( anemia ).

Inhibitor of atp synthase

Bedaquiline, representing the synthetic antibacterial class of compounds called the diarylquinolones , uses a novel mode of action that specifically inhibits mycobacterial growth. Although the specific mechanism has yet to be elucidated, this compound appears to interfere with the function of ATP synthases, perhaps by interfering with the use of the hydrogen ion gradient for ATP synthesis by oxidative phosphorylation , leading to reduced ATP production. Due to its side effects , including hepatotoxicity and potentially lethal heart arrhythmia, its use is reserved for serious, otherwise untreatable cases of tuberculosis .

To learn more about the general principles of antimicrobial therapy and bacterial modes of action, visit Michigan State University’s Antimicrobial Resistance Learning Site , particularly pages 6 through 9.

Key concepts and summary

• Antibacterial compounds exhibit selective toxicity , largely due to differences between prokaryotic and eukaryotic cell structure.
• Cell wall synthesis inhibitors, including the β-lactams , the glycopeptides , and bacitracin , interfere with peptidoglycan synthesis, making bacterial cells more prone to osmotic lysis.
• There are a variety of broad-spectrum, bacterial protein synthesis inhibitors that selectively target the prokaryotic 70S ribosome, including those that bind to the 30S subunit ( aminoglycosides and tetracyclines ) and others that bind to the 50S subunit ( macrolides , lincosamides , chloramphenicol , and oxazolidinones ).
• Polymyxins are lipophilic polypeptide antibiotics that target the lipopolysaccharide component of gram-negative bacteria and ultimately disrupt the integrity of the outer and inner membranes of these bacteria.
• The nucleic acid synthesis inhibitors rifamycins and fluoroquinolones target bacterial RNA transcription and DNA replication, respectively.
• Some antibacterial drugs are antimetabolites , acting as competitive inhibitors for bacterial metabolic enzymes. Sulfonamides and trimethoprim are antimetabolites that interfere with bacterial folic acid synthesis. Isoniazid is an antimetabolite that interferes with mycolic acid synthesis in mycobacteria.

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