Living Textbook MC610

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Agents Acting on Cell Membrane

There are two types that fall under this heading:

1. Systemic Agents:

These are important antibiotics used systemically.

Daptomycin (Cubicin®), shown below, is a cyclic lipoprotein used against Gram positive infections, as it is too large and lipophilic to cross the Gram negative bacterial cell wall and binds to phosphatydyl glycerol, that is not present in high amounts in Gram negative bacteria. It acts by inserting its tail into the cell membrane, specifically to the phosphatydyl glycerol, dissipates membrane potential and causes an efflux of potassium. It is used as the last resort for serious and resistant Gram positive infections such as MRSA.

Colistin belong to polymyxin family that is now used systemically despite its toxicity in case of multiresistant Gram negative bacterial infections. Polymyxins are discussed below.

2. Antiseptics and Disinfectants:

These agents are used externally due to their high level of toxicity. They are intended to kill microorganisms (bactericidal agents) and have a wide spectrum of activity (antibacterial, fungal and viral effects). They either act on the surface of the body (antiseptic) or on inanimate objects (disinfectants). Most of these agents act by disrupting cell membrane, allowing ions and nutrients to leak out or cause cell lysis.

They are mostly toxic agents and not useful systemically, but are useful in a wide range of products ranging from soaps to deodorants to sunburn products, foot powders, surgical cleansers...etc.


These agents act by forming a hydrogen bond through the hydroxyl group with the esters of the phospholipids, and a hydrophobic interaction between the side chain and the lipids in the cell membrane. Activity of these agents increase as the number of carbon atoms in the side chain increases until it reaches about 8 to 10 carbon units, then starts to diminish.

Examples are ethanol and isopropanol, the latter preferred in many cases as a cheaper, more effective alternative but with higher toxicity. A 70% concentration of the alcohol is usually used as it is said to give better wettability and aid in penetration into the cell membranes. It is also a good concentration for antiviral activity.


Probably the standard for all antiseptics and disinfectants. Introduced in the 19th century by Lister and has been used since. We still use phenol coefficient as a standard today.

This class that includes xylenols and cresols bind to the cell membrane similar to alcohols. They cause precipitation of proteins at lower concentration and lead to cell lysis at higher concentration. Substitutions on the phenyl ring, especially para to the hydroxyl group improves activity. The higher the lipophilicity, the more effective the agent, but we have to also consider water solubility. They are effective against most bacteria, fungus and some viruses.

Cationic Antiseptics

These agents contain a very basic amine that is protonated or permanently positively charges (a quaternary amine) and a lipophilic side chain. The amine binds to phosphates on the cell membrane, and the lipophilic side chain forms hydrophobic interactions with membrane lipids, forming a stable complex. This complex will interfere with many membrane enzymes and functions, inhibit uptake of cations in particular potassium and aid in leakage of ions, nucleotides and sugars out of the cells. Their efficiency increases with a rise in pH.


Cetrimide, a 14-carbon chain is the optimal length. It has detergent properties as well. It is not effective against pseudomonas and proteus species.

Benzalkonium Chloride, where the side chain is an 8-20 carbon chain, that may include aryl groups

Chlorohexidene, binds very strongly to the membrane and is less irritant than other cationic antiseptics. Used in mouthwashes to fight streptococcus mutans, which may fight plaque, teeth infections and even caries.

Triclosan, shown below, inhibits the enzyme enoyl-acyl carrier protein reductase (ENR) forming a ternary complex: ENR-NAD+-triclosan, that causes cell membrane disruption. It is used in a number of products such as mouth wash, soaps and shampoos. The FDA recently issued a ban of the use of triclosan and other antiseptics in some of these products, although it did not ban these agents themselves.


These agents bind very strongly to the cell membrane and disrupts its functions. These agents bind to the membrane in a similar way to cationic antiseptics. They do seem to displace magnesium in the membrane, which is important for membrane stability, and is important for many vital biochemical processes.

Gramicidin S is a decapeptide that is effective against Gram positive.

Polymyxin is a small cyclic and branched fatty acid that is effective against Gram negative bacteria. It is actually used systematically by injection in severe Gram negative infection such as those caused by pseudomonas, but must be aware of its nephrotoxicity. As mentioned above, they are now used systemically for resistant bacterial infections.

The cyclic structure, its size and the presence of the basic groups are essential for activity. The amino acids can be changed, but need to restore the size basic nature of some of the amino acids.


They are cyclic amino acids that form ion-permeable pores that facilitate the leakage of ions out of the cells. They are effective mostly against Gram positive bacteria. The alternating D- and L- conformation of the amino acids is essential to give a cylindrical conformation with the polar components inside to interact with the cations, and the hydrophobic moieties outside to interact with the membrane. They are mostly used in veterinary medicine and in animal husbandaries due to their toxicity.

Examples include Valinomycin. and Gramicidin A.

Oxidizing Agents

These agents act by denaturing proteins, and are used to clean wounds.

Examples include Hydrogen Peroxide and Permanganate salts


They all contain iodine (I2). They cause the iodination of certain amino acids such as Tyrosine and Phenylalanine and oxidation of disulfide bridges in proteins. They are excellent agents that are effective against bacteria, fungus, protozoa and viruses.

Iodine solution and iodine tincture are useful, but stain the skin and can be toxic.

Povidene Iodine (Betadineâ ) allows the slow release of iodine. It has many uses ranging from applying to skin before surgery, to wound cleaning to mouthwash preparations. It is available in many forms, aerosols, creams, solutions?etc.


Mostly cationic in nature, interact with the acidic component of the membranes. Examples include Gentian Violet, Methylene Blue and Fuchsine. They are effective against Gram positive bacteria (same principle as the Gram stain).

Mercury-containing Compounds

Mercury will precipitate proteins, but it is toxic. Users should be advised to avoid contact with tissues or skin.