Living Textbook MC610

Select Topic:

Unclassified Antibiotics

1. Chloramphenicol

First isolated from Streptomyces sp. in 1947, this antibiotic has a very broad spectrum including Gram positive, negative, Ricketseae and Chlamydia. It has a very unusual aryl nitro group and dichloroacetamide group. This agent is now produced by total synthesis.

Mechanism of Action:

Binds to the 50S subunit, in a spot close to where Macrolides bind, and prevents attachment of amino acyl tRNA to the ribosome. It is not clear if it blocks the A- or P-site, but recent evidence point to the former resulting in inhibiting peptidyl transferase. The mammalian ribosome is relatively unaffected. It is a bacteriostatic agent.

Structure Activity Relationship:

Not many changes can be afforded to this compound. The nitro group can be replaced with other electron withdrawing groups but activity declines. The aromatic ring is essential. Removing the chlorines or replacing them with other halogens reduces activity. From the four diastereomers, only the D-threo (1R, 2R) compound is active. This may be due to a formation of a hydrogen bond that forms a pseudo sugar-like ring that may be important for binding and activity.


Inactivating enzymes that cause acetylation of the hydroxyl groups (especially the secondary alcohol), resulting in a decreased ability of binding to the ribosomes. Another mechanism is decreased permeability, which is seen in E.coli.


Metabolism of this agent is extensive and rapid, resulting in a relatively short half-life. Metabolism is mainly through the formation of the C3-glucuronide metabolite that is the soluble excretable metabolite. The reduction of the nitro compound to the amine, dechlorination and the hydrolysis of the amide bond may also occur. All these metabolites are inactive.

Pharmacokinetic Properties:

Chloramphenicol is an uncharged, neutral and moderately water-soluble molecule. It is well absorbed then well distributed to tissues, including the CSF, lymph and mesentric ganglions. It shows about 60% protein binding. It has a bitter taste, which can be masked by the use of the palmitate ester at the 3-hydroxy group in pediatric oral suspensions. The soluble hemisuccinate sodium ester is used in the injectable forms, where IV route is preferred as cleavage of the prodrug is slow in muscles.


It can cause a dose-related bone marrow depression and agranulocytosis, which are reversible, and are more common in elderly patients or those with renal insufficiency. A very small percent of patients (one in every 25,000 to 40,000 cases of therapy) may develop aplastic anemia, which is enhanced by genetic disposition and results from loss of both white and red cells precursors. This is a very dangerous side effect that is dose-independent and has been reported to occur following the use of the ophthalmic preparation. It is irreversible and may be fatal due to cardiovascular collapse. The underlying factor is not clear and may involve the inhibition of the mitochondrial ribosome that resembles the bacterial 70S ribosome. Another interesting theory is that an intermediate formed during the reduction of the nitro group, which can interact with the ferrous ion in hemoglobin and oxidizes it to the ferric state that is incapable of carrying oxygen.

In the newly born if this agent is given within the first 48 hours of life, Gray syndrome may arise due to the inability of formation of the 3-glucuronide metabolite, resulting in toxic levels of the drug, profound anemia, a gray pallor and cyanosis resulting in cardiovascular collapse and death.

Due to these dangerous side effects Chloramphenicol is restricted to serious infections such as paratyphoid, typhoid fever (owing to their ability to penetrate the lymph and ganglions) and meningitis (owing to their ability to penetrate the CSF) resistant to ß-lactams or in patients allergic to these agents. However in some countries it is very popular as an inexpensive and efficient agent.

2. Fusidic Acid

This agent belongs to a family of agents that display the steroid structure. It inhibits protein biosynthesis at the translocation step of the amino acyl tRNA from the A-site to the P-site by interfering with one of the elongation factors that is important for this step. It can also inhibit protein synthesis in mammalian cells through the same mechanism, but selective toxicity appears to be due to its inability to gain access to mammalian cell's cytoplasm. It is effective against many Gram positive agents, but not Gram negative due to low penetration ability into the cytoplasm. It is mostly used in staphylococcus infection, in many cases with Penicillins to overcome the emerging problem of resistance that is said to have been accelerated due to the wide use of the topical preparation.

3. Mupirocin

A lipid acid antibiotic that is isolated from pseudomonas sp. It is mostly used topically as it is rapidly hydrolyzed in vivo. It has a broad spectrum but mostly used against Staphylococcal and Streptococcal skin infections. It binds and competitively inhibits the isoleucyl-tRNA synthase and thus prevents incorporation of isoleucine into bacterial proteins. Resistance arises through mutations to the synthase, resulting in poor binding of the drug to the enzyme.

4. Oxazolidinones

These agents contain an oxazolidinone ring and are being touted as the first novel antimicrobial agents in thirty years. Linezolid (Zyvoxâ ) was approved in 2000 for use in nosocomial Gram positive infections, especially against MRSA, VRE, pneumonia and multiresistant strains. They are bacteriostatic agents that inhibit protein synthesis at a different stage than any other agent known. They inhibit the initiation at the translation level and prevent the formation of the fmet-tRNA:mRNA:30S complex, possibly by distorting the binding site of the initiator tRNA. They bind to the same site as Chloramphenicol on the 50S subunit, but do not inhibit Peptidyl Transferase. They are used orally or by IV and already some resistant strains have been reported. The main toxic effect reported are some CNS disorders and some cases of anemia.

5. Daptomycin

Daptomycin is a lipopeptide antibacterial agent that is reported to have a spectrum of antibacterial activity similar to that of Vancomycin and greater potency against many Gram positive bacteria.
It is a bactericidal agent that acts via a novel mechanism of action. Structurally, Daptomycin is a cyclic lipopeptide, with a 10-amino acid ring and a tail comprised of 3 amino acids and a lipid chain of 10 carbon atoms. Daptomycin initially attacks bacteria by inserting its "tail" into the cell membrane of Gram-positive bacteria in a calcium-dependent manner. Daptomycin does not lyse bacteria, nor does it enter the cytoplasm, but rapidly dissipates bacterial membrane potential, which is essential for cell viability and causes ion movements across the bacterial membrane and a dose-dependent efflux of potassium that correlates to the killing of the bacteria. The antibacterial activity of Daptomycin is dependent on the presence of free calcium ions that binds to and increases the hydrophobicity of Daptomycin, facilitating the insertion of the "tail" into the bacterial membrane.