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Antibiotic Mechanisms
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Antibiotic Mechanisms

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Key Definitions
Broad-spectrum vs. Narrow-spectrum* – Broad-spectrum antibiotics are active against a wide range of bacteria. – Narrow-spectrum antibiotics are active against a narrower range of bacteria. Intermediate-spectrum fall somewhere in between.
  • Bacteriostatic antibiotics inhibit bacterial growth.
– The minimum inhibitory concentration of a bacteriostatic drug is the lowest concentration of antibiotic that inhibits bacterial growth.
  • Bactericidal antibiotics kill the bacteria.
– The minimum bactericidal concentration is the lowest concentration of antibiotic that will kill 99.9% of the bacterial population.
  • Combined Effects
– Antagonism: the antibiotic effects are reduced upon combination. – Synergism: the antibiotic effects are enhanced when drugs are combined: For example, some combinations can broaden the antibiotic spectrum; Or, some combinations prevent the development of antibiotic resistance.
Antibiotic Mechanisms
To visualize where antibiotic effects occur, we draw a simplified bacterial cell, including the cell wall and plasma membrane, ribosomes, and the nucleoid, which is the region of the bacterial cell where the genetic material resides.
Antibiotics that act on the cell wall and plasma membrane
Beta-lactams interfere with synthesis of the peptidoglycan layer of the cell wall. – More specifically, beta-lactams bind transpeptidases, which are bacterial enzymes required for peptidoglycan crosslinking. – It's helpful to know that, because they are the targets of penicillins and other beta-lactams, the transpeptidases are also called Penicillin-Binding Proteins! – Penicillinase is a bacterial enzyme that renders penicillin ineffective.
Penicillins Penicillins that are Sensitive to penicillinase:
  • Penicillin G
  • Penicillin V
  • Ampicillin
  • Amoxicillin.
Penicillins that are Resistant to penicillinase
  • Oxacillin
  • Nafillin
  • Dicloxacillin.
Non-Penicillin Beta-lactams
– Imipenem – Menopenem – Ertapenem – Doripenem
  • A monobactam called aztreonam
Non-Beta-lactams also act on the cell wall or plasma membrane in the following ways:
Interfere with peptidoglycan synthesis:
Bind to the plasma membrane: Lipopeptide
Polymyxins
  • Polymyxin B
  • Polymyxin E (aka, colistin)
Target the cell walls of mycobacteria:
Antibiotics that act on bacterial ribosomes
These drugs disrupt protein synthesis.
Act on30S subunit:
– Gentamycin – Neomycin – Amikacin – Tobramycin – Streptomycin
– Tetracycline – Doxycycline – Minocycline
– Tigecycline
Act on50S subunit:
– Azithromycin – Erythromycin – Clarithromycin
– Clindamycin
– Linezolid
Antibiotics that inhibit folic acid production (aka, Antimetabolites)
Recall that mammalian cells do not synthesize folic acid, thus, these antibiotics do not interfere with our cellular metabolism.
– Sulfamethoxazole – Sulfisoxazole – Sulfadiazine
  • Another antimetabolite drug is trimethoprim;
– Often administered with sulfamethoxazole (TMP/SMX, aka, Bactrim). – This is an example of antibiotic synergism that enhances bactericidal effects.
  • Anti-Mycobacteria
– Dapsone – Para-aminosalicyclic acid
Antibiotics that interfere with bacterial DNA/RNA
Inhibit DNA Synthesis:
  • Quinolone
– Nalidixic acid
– Ciprofloxacin – Levofloxacin – Moxifloxacin
Disrupts bacterial DNA integrity: – Metroniadazole
Interferes with RNA synthesis:
– Rifampin
These drugs are commonly used in treatment of Mycobacterial infections.
Mechanisms of Resistance
Antibiotic resistance can be intrinsic* – The mechanism of resistance is inherent to the structure or physiology of the bacteria. – For example, a bacterium that does not have penicillin-binding proteins will be insensitive to penicillins. Antibiotic resistance can be acquired* – The mechanism is acquired via mutations in bacterial chromosomal genes or horizontal gene transfer. – For example, the genes for antibiotic resistance can be found on plasmids that are easily transferred among bacteria.
Key Mechanisms:
Be aware that bacteria may use multiple forms of resistance.
  • Some bacteria produce enzymes that modify or destroy the antibiotic.
– For example, Aminoglycoside modifying enzymes (AMEs) render the aminoglycoside antibiotics ineffective by altering the chemical structure of the drugs, rendering them ineffective. – Beta-lactamases, on the other hand, destroy bonds of the beta-lactam ring.
  • Bacteria can also prevent drugs from reaching their targets; this is an especially effective mechanism against antibiotics that target the cytoplasmic membrane or intracellular structures.
– For example, E. coli can reduce membrane permeability via porin changes. – Or, bacteria can increase production of efflux pumps, which extrude antibiotic molecules. For example, E. coli can upregulate these pumps to effectively decrease the cytoplasmic concentration of tetracycline.
  • Modification of the drug's target to bypass or alter affinity is another effective means of resistance.
– As an example of altered affinity, Methicillin-Resistant Staphylococcus aureus (MRSA) has a low-affinity version of the Penicillin-binding Protein; thus, beta-lactams are ineffective. – As an example of bypassing a drug's target, fluoroquinolone resistance is achieve via alteration in the genes for the drugs' target enzymes.
  • Complex changes in bacterial cell physiology can also lead to global resistance.
– For example, multi-step resistance acquisition appears to play an important role in resistance to daptomycin and vancomycin.

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