Disruptors of Cell Membranes: Videos & Practice Problems

Lipopeptide antibiotics like polymyxin B and polymyxin E (colistin) disrupt gram-negative bacterial cell membranes by binding to lipopolysaccharides and inserting hydrophobic tails, causing membrane leakage. Polymyxin B is a topical, over-the-counter antibiotic effective against gram-negative bacteria, while polymyxin E is a nephrotoxic, last-resort drug for resistant infections. These drugs exemplify selective toxicity by targeting unique bacterial membrane components absent in gram-positive bacteria, highlighting their role in combating antibiotic resistance and maintaining therapeutic efficacy in treating gram-negative bacterial infections.

Disruptors of Cell Membranes

Understanding how certain antibiotics disrupt bacterial cell membranes is crucial for targeting infections effectively while maintaining selective toxicity. Bacterial cell membranes share similarities with human cell membranes but contain unique lipids, such as lipopolysaccharides in gram-negative bacteria, which serve as specific targets for some antibiotics. Lipopeptides are a class of drugs that bind to these distinctive components, disrupting the membrane integrity and causing leakage that ultimately kills the bacterial cell.

Gram-negative bacteria are characterized by a double membrane structure with an outer membrane containing lipopolysaccharides. Lipopeptide antibiotics, such as polymyxin B and polymyxin E (also known as colistin), exploit this feature by binding to the lipopolysaccharides. Their hydrophobic tails insert into the lipid bilayer, destabilizing both the outer and inner membranes, leading to increased permeability and cell death. This mechanism makes these drugs effective primarily against gram-negative bacteria, as gram-positive bacteria lack lipopolysaccharides and thus are not susceptible to this mode of action.

Polymyxin B is commonly used as a topical antibiotic for skin infections and is often found in over-the-counter ointments like Neosporin. Its accessibility and safety profile allow for widespread use against gram-negative bacterial infections on the skin. In contrast, polymyxin E (colistin) is reserved as a drug of last resort for severe infections caused by multidrug-resistant gram-negative bacteria. Due to its nephrotoxicity and narrow therapeutic window, colistin requires careful monitoring during treatment. Limiting its use also helps prevent the development of antibiotic resistance, preserving its effectiveness for critical cases.

To differentiate between these two similar drugs, one can remember that polymyxin B is for "basic" use, reflecting its common availability, while polymyxin E is for "extraordinary" use, highlighting its role as a last-resort antibiotic. Both drugs share the same fundamental mechanism of disrupting gram-negative bacterial membranes but differ significantly in their clinical applications and safety considerations.

William has a bacterial infection from a cut on his leg, and his doctor has identified the cause as a Gram-negative strain of bacteria. Which of the following would be the most appropriate antimicrobial for the doctor to recommend to William?

• A. Polymyxin B, because it is typically used as a topical treatment for a broad range of Gram-negative bacteria.
• B. Polymyxin E, because it will be more effective for a skin infection than polymyxin B.
• C. A combination of both polymyxin B & polymyxin E should be used, as they are synergistic.
• D. Neither polymyxin B nor polymyxin E would be appropriate for a Gram-negative skin infection.

Answer: (A)

Some types of Gram-negative bacteria are less susceptible to polymyxin B and polymyxin E. Which of the following could explain why that is the case?

• A. Unlike other Gram-negative bacteria, these bacteria do not have an outer cell membrane.
• B. The bacteria have lipopolysaccharides that do not bind to polymyxin B or polymyxin E as effectively.
• C. The bacteria have a cell wall that uses a unique mechanism to cross-link peptidoglycan strands.
• D. These bacteria have a unique porin structure that reduces the amount of antibiotic that can enter the cell.

Answer: (A)

Many first-aid antibiotic ointments, such as the bran-name product Neosporin®, contain bacitracin, neomycin (an aminoglycoside), and polymyxin B. Based on your knowledge of these drugs, which of the following answer choices best completes the statement below?
Together, these drugs can be expected to:

• A. Be very broad-spectrum, as bacitracin is effective against Gram-positive bacteria, neomycin is broad-spectrum, and polymyxin B is effective against Gram-negative bacteria.
• B. Be more effective since they act on multiple cellular targets: bacitracin targets the ribosomes, neomycin targets the cell wall, and polymyxin B targets the cell membrane.
• C. Works synergistically, as all three drugs target the same cellular pathway but at a different steps.
• D. Works synergistically, as all three drugs have similar spectrums, allowing them to target the same bacteria.

Answer: (A)

Here’s what students ask on this topic:

What are lipopeptide antibiotics and how do they disrupt bacterial cell membranes?

Lipopeptide antibiotics are a class of drugs that target bacterial cell membranes by binding to specific components unique to bacteria. They disrupt the membrane by attaching to lipopolysaccharides (LPS) found in the outer membrane of gram-negative bacteria. These antibiotics have hydrophobic tails that insert into the membrane, creating pores or leaks. This disruption causes the membrane to become permeable, leading to leakage of cellular contents and ultimately bacterial cell death. Because human cell membranes lack LPS, lipopeptides exhibit selective toxicity, targeting bacteria without harming human cells. Examples include polymyxin B and polymyxin E (colistin), which are effective primarily against gram-negative bacteria due to this mechanism.

Why are polymyxin B and polymyxin E only effective against gram-negative bacteria?

Polymyxin B and polymyxin E (colistin) are effective only against gram-negative bacteria because they specifically target lipopolysaccharides (LPS), which are unique components of the outer membrane of gram-negative bacteria. Gram-positive bacteria lack this outer membrane and LPS, so these drugs cannot bind or disrupt their membranes. The binding to LPS allows polymyxins to insert their hydrophobic tails into the membrane, causing leakage and cell death. This selective targeting explains why polymyxins are ineffective against gram-positive bacteria but are potent against gram-negative pathogens.

What is the difference between polymyxin B and polymyxin E (colistin) in terms of usage and toxicity?

Polymyxin B and polymyxin E (colistin) differ mainly in their clinical use and toxicity profiles. Polymyxin B is commonly used as a topical antibiotic, often found in over-the-counter ointments like Neosporin, for treating skin infections caused by gram-negative bacteria. It is considered safe for general use. In contrast, polymyxin E, or colistin, is a drug of last resort used to treat severe infections caused by multidrug-resistant gram-negative bacteria. Colistin has significant nephrotoxicity (kidney toxicity), requiring careful monitoring during treatment. Due to its toxicity and the risk of resistance development, colistin is reserved for cases where other antibiotics fail.

How does selective toxicity apply to lipopeptide antibiotics like polymyxins?

Selective toxicity refers to the ability of an antibiotic to target bacterial cells without harming human cells. Lipopeptide antibiotics like polymyxins achieve selective toxicity by binding specifically to lipopolysaccharides (LPS), which are unique to the outer membrane of gram-negative bacteria. Human cells do not have LPS, so polymyxins do not disrupt human cell membranes. This selective binding allows these drugs to kill bacteria by disrupting their membranes while minimizing damage to human tissues. This principle is crucial in antibiotic design to maximize effectiveness and reduce side effects.

Why is colistin considered a drug of last resort, and what precautions are necessary when using it?

Colistin (polymyxin E) is considered a drug of last resort because it is used to treat infections caused by multidrug-resistant gram-negative bacteria when other antibiotics fail. Its use is limited due to its nephrotoxicity, meaning it can cause kidney damage, and it has a narrow therapeutic window. To prevent the development of resistance and minimize toxicity, colistin is reserved for severe cases and requires careful dosing and monitoring of kidney function during treatment. This cautious approach helps preserve its effectiveness and protect patient safety.