Antibacterial pharmacology — Polymyxins: What is the principal mode of action of polymyxin antibiotics (e.g., polymyxin B and colistin) against susceptible bacteria?

Introduction / Context:
Polymyxins are last-line antibiotics used primarily against multidrug-resistant Gram-negative bacilli. Understanding their mechanism helps predict activity spectrum, synergy, and toxicity profiles in clinical microbiology and pharmacology exams.

Given Data / Assumptions:

• The drug class is polymyxins (e.g., polymyxin B, colistin/polymyxin E).
• Target organisms are mainly Gram-negative bacteria with lipopolysaccharide-rich outer membranes.
• We must identify the key mechanism of antibacterial action.

Concept / Approach:
Polymyxins are cationic cyclic polypeptides that bind to lipid A of lipopolysaccharide and displace stabilizing divalent cations. This disrupts outer membrane integrity and then the inner (plasma) membrane, increasing permeability and causing leakage of essential cytoplasmic contents. The net result is rapid bactericidal activity due to membrane injury rather than inhibition of intracellular biosynthetic pathways.

Step-by-Step Solution:
Recognize polymyxins as membrane-active cationic detergents. Note primary binding to lipid A in Gram-negative outer membrane. Progression to plasma membrane disruption causes ion leakage and cell death. Therefore, the principal action is direct injury to the plasma membrane.

Verification / Alternative check:
Laboratory assays show immediate release of potassium and other intracellular solutes after polymyxin exposure. Time-kill curves demonstrate rapid bactericidal effects consistent with membrane disruption rather than slower inhibition of macromolecular synthesis.

Why Other Options Are Wrong:

• Inhibition of protein synthesis: characteristic of macrolides, lincosamides, oxazolidinones, and aminoglycosides (30S/50S effects), not polymyxins.
• Inhibition of DNA synthesis: typical for fluoroquinolones and some antimetabolites.
• Inhibition of folic acid synthesis: mechanism of sulfonamides and trimethoprim.

Common Pitfalls:
Confusing polymyxins with aminoglycosides because both target Gram-negatives; however, aminoglycosides inhibit protein synthesis at the 30S subunit, while polymyxins disrupt membranes.

Final Answer:
Direct injury to the bacterial plasma (cytoplasmic) membrane