Antimicrobial Mechanisms

Overview: four targets

The map. Antibacterials act at one of four sites: the cell wall (beta-lactams, vancomycin), the 30S ribosomal subunit (aminoglycosides, tetracyclines), the 50S subunit (macrolides, clindamycin, linezolid, chloramphenicol), or DNA and its folate supply (fluoroquinolones, metronidazole, sulfonamides and trimethoprim). The target predicts the spectrum, whether the drug kills or only halts growth, and much of its toxicity.

Selective toxicity. Bacteria have a peptidoglycan wall that human cells lack, 70S ribosomes (30S + 50S) rather than the 80S ribosomes of human cytoplasm, and they must make their own folate. Human mitochondrial ribosomes resemble bacterial ones, which helps explain the dose-related marrow suppression of chloramphenicol and the lactic acidosis and neuropathy of prolonged linezolid use.

"Buy AT 30, CCEL at 50": Aminoglycosides and Tetracyclines bind 30S; Chloramphenicol, Clindamycin, Erythromycin (macrolides) and Linezolid bind 50S.

Cell wall synthesis inhibitors

Beta-lactams. Penicillins, cephalosporins, carbapenems and monobactams bind penicillin-binding proteins (PBPs), the transpeptidases that cross-link peptidoglycan. The weakened wall and activated autolytic enzymes lyse the cell, so they are bactericidal. Killing is time-dependent: what matters is how long free drug stays above the MIC, not the peak level. Beta-lactamases hydrolyze the beta-lactam ring; adding an inhibitor such as clavulanate (or sulbactam, tazobactam, avibactam) protects the drug.

Vancomycin. This large glycopeptide binds the D-Ala-D-Ala terminus of peptidoglycan precursors and blocks their incorporation, halting wall elongation. It is bactericidal against gram-positives only, because it is too large to pass through gram-negative porins. It covers MRSA, and oral vancomycin, which is not absorbed, treats C. difficile colitis. Toxicity: nephrotoxicity, ototoxicity and red man syndrome, which is flushing from direct histamine release during rapid infusion. Slowing the infusion prevents it; it is not a true allergy. Enterococci resist by changing the terminus to D-Ala-D-Lac (VRE).

Protein synthesis inhibitors

Aminoglycosides. Gentamicin, neomycin, amikacin, tobramycin and streptomycin ("GNATS") bind 30S irreversibly, block formation of the initiation complex and cause mRNA misreading. They are bactericidal and concentration-dependent, and they synergize with beta-lactams, which damage the wall and speed their entry. Uptake is oxygen-dependent, so they are useless against anaerobes ("mean GNATS canNOT kill anaerobes"). Toxicity: nephrotoxicity, ototoxicity (worse with loop diuretics), neuromuscular blockade (dangerous in myasthenia gravis) and teratogenicity.

Tetracyclines. Tetracycline, doxycycline and minocycline bind 30S and block aminoacyl-tRNA from entering the A site; they are bacteriostatic. Doxycycline is eliminated in feces, so it is safe in renal failure. Divalent cations in milk, antacids and iron supplements chelate the drug and block its absorption. Tetracyclines also bind calcium in growing teeth and bone, causing tooth discoloration and inhibited bone growth, and they cause photosensitivity, so they are avoided in children and pregnancy.

Macrolides. Azithromycin, clarithromycin and erythromycin bind the 23S rRNA of the 50S subunit and block translocation. They are bacteriostatic and cover atypicals (Mycoplasma, Chlamydia, Legionella). Toxicity follows "MACRO": GI Motility problems (erythromycin stimulates motilin receptors), Arrhythmia from long QT, acute Cholestatic hepatitis, Rash and eOsinophilia. Erythromycin and clarithromycin inhibit CYP450 and raise levels of drugs such as warfarin and theophylline.

Clindamycin. It binds 50S and blocks translocation. It covers anaerobes above the diaphragm (aspiration pneumonia, lung abscess), whereas metronidazole covers those below. Because it stops protein synthesis, it shuts off toxin production in invasive group A strep infection and gas gangrene. Its classic toxicity is C. difficile pseudomembranous colitis.

Linezolid and chloramphenicol. Linezolid binds 50S and prevents formation of the initiation complex; it is reserved for MRSA and VRE. Toxicity: thrombocytopenia, peripheral neuropathy and serotonin syndrome, since it weakly inhibits MAO. Chloramphenicol blocks 50S peptidyltransferase. It causes dose-independent aplastic anemia and gray baby syndrome: neonates lack hepatic UDP-glucuronosyltransferase, cannot conjugate the drug, and develop gray cyanosis, hypotension and circulatory collapse.

DNA and folate inhibitors

Fluoroquinolones. Ciprofloxacin and levofloxacin inhibit DNA gyrase (topoisomerase II) and topoisomerase IV, so bacteria can neither relieve supercoiling nor separate replicated chromosomes. They are bactericidal, with strong gram-negative and Pseudomonas coverage. Toxicity: tendinopathy and tendon rupture (higher risk in the elderly and with corticosteroids), cartilage damage (avoid in children and pregnancy) and QT prolongation. Like tetracyclines, they are chelated by cations.

Metronidazole. Inside anaerobes and protozoa the drug is reduced to toxic free radicals that damage DNA; it is bactericidal. Coverage follows "GET GAP on the Metro": Giardia, Entamoeba, Trichomonas, Gardnerella, Anaerobes below the diaphragm (Bacteroides, C. difficile) and H. pylori. Toxicity: a disulfiram-like reaction with alcohol (flushing, vomiting, tachycardia) and a metallic taste.

Sulfonamides and trimethoprim. Sulfonamides are PABA analogs that inhibit dihydropteroate synthase; trimethoprim inhibits bacterial dihydrofolate reductase. Humans take in preformed dietary folate, so the first enzyme is a bacteria-only target. Combined as TMP-SMX, the sequential blockade is bactericidal.

Folate-antagonist toxicity. Sulfonamides cause hypersensitivity including Stevens-Johnson syndrome, hemolysis in G6PD deficiency, photosensitivity and kernicterus in neonates, because they displace bilirubin from albumin. Trimethoprim causes megaloblastic anemia and other marrow suppression, which folinic acid (leucovorin) offsets. It also causes hyperkalemia by blocking collecting-duct sodium channels, as amiloride does.

Bactericidal versus bacteriostatic

The lists. Bactericidal: penicillins, cephalosporins, vancomycin, aminoglycosides, fluoroquinolones, metronidazole, isoniazid and rifampin. Bacteriostatic ("ECSTaTiC"): erythromycin, clindamycin, sulfamethoxazole, trimethoprim, tetracyclines and chloramphenicol, plus linezolid. Cidal drugs are preferred when host defenses cannot finish the job, as in endocarditis, meningitis and neutropenia.

Aminoglycosides are the odd ones out: the only bactericidal protein synthesis inhibitors.