Sulfonamides and Sulfonamide Hapten

 Due to a low cost and general efficacy in common bacterial diseases, sulfonamides (SAs), the oldest antibacterial agents, are still widely used nowadays in human and veterinary medicine for the treatment and prophylactic purposes of infectious diseases and used as growth-promoting feed additives.

 

General Properties of SAs

 

Sulfonamides (SAs), derivatives of sulfanilamide, which is the nucleus common to all sulfonamides, are a large group of antimicrobial synthetic chemotherapeutic drugs. SAs are synthesized by adding or substituting different functional groups to the amido group or other amino groups, leading to compounds with a variety of physical, chemical, pharmacologic, and antibacterial properties.

 

Currently, over 30 sulfonamides are used as antimetabolites in human and animal treatment, in a mechanism of blocking several enzymes that are needed for the biosynthesis of purine bases and necessary metabolic reactions for the formation of RNA. The bacteriostasis effect occurs once bacteria use up existing stores of folic acid, folinic acid, purines, thymidine, and amino acids, causing inhibition of the protein synthesis, metabolic processes, and growth and replication of bacteria in organisms.

 

However, hypersensitivity or direct toxic effects could cause serious adverse reactions to sulfonamides, including urticaria, angioedema, anaphylaxis, skin rashes, drug fever, polyarthritis, hemolytic anemia, and agranulocytosis.

 

Sulfonamide-specific Haptens

 

Given that the immune system involves in these adverse reactions, researchers suggested that drug haptens may be important in the pathogenesis of these reactions. According to the definition of haptens that small molecules elicit an immune response and stimulate the production of antibodies against small molecules only when conjugated to a large carrier such as a protein, small compounds like sulfonamide drugs can be classified as haptens.

 

SAs are too small as a synthetic immunogen to elicit an immune response. But a conjugation to proteins can make sulfonamides immunogenic for the generation of anti-SAs antibodies. A strategy involving in the sulfonamides hapten design and synthesis is the attachment of the hapten with protein carriers via the common aromatic amino group of all SAs.

 

As previously described, sulfonamides share the common chemical nucleus of sulfanilamide, in which sulfonamides are usually defined as N1-position or N4-position substituted compounds, depending on the substitution of the amido (designated as N1) or aromatic (designated as N4) amino group.

 

The inherent heterogeneity of sulfonamide-specific haptens decides that antibodies produced by the sulfonamide-protein conjugates immunized animals are likely to react to other haptens with a similar structure, resulting in cross-resistance to sulfonamides in many animal populations. But scientists believe that such cross-reactivity can be potentially characterized for class-specific applications. Intending to develop generic antibodies, researchers have focused on the structure and orientation of SAs within the immunogen and found that common amino-benzene-sulfonamide moiety is at the immunodominant position by linking to pyrimidinyl, pyridinyl, benzyl ring, and other structures at the N1 position. 

 

That's to say, chemical substitution at the N1 position can be means of synthesizing antibodies, while a protein connection at the N4 end in antigen synthesis can expose the pyrimidine ring at the N1 end so that the body can produce antibodies with high-affinity and class-specific against SAs after immunizing compound-specific haptens for sulfonamides.

 

Applications

 

Sulfonamides are widely used to inhibit both gram-positive and gram-negative bacteria, Nocardia, Actinomyces spp, and some protozoa such as coccidia and Toxoplasma spp. What's more, highly active sulfonamides may be used against several species of Streptococcus, Staphylococcus, Salmonella, Pasteurella, and even Escherichia coli in their spectra.

 

Despite the overall positive antimicrobial and growth-promoting effects in the animal industry and aquaculture, inappropriate levels of sulfonamides when used to treat livestock, fish and shrimp diseases are prone to become undesirable residues in tissues, biofluids, and environmental water samples. As a result, the presence of sulfonamide residues in foods of animal origin is increasingly becoming a potential health hazard for humans.