Sulfadimethoxine: Antimicrobial Activity, Protein Binding, and Immune-Modulatory Effects

Sulfadimethoxine is a sulfonamide consisting of pyrimidine having methoxy substituents at the 2- and 6-positions and a 4-aminobenzenesulfonamido group at the 4-position. It has a role as an antiinfective agent, an antimicrobial agent, a xenobiotic, an environmental contaminant and a drug allergen. It is a member of pyrimidines, a sulfonamide, a substituted aniline, an aromatic ether and a sulfonamide antibiotic. It is functionally related to a sulfanilamide. Sulfadimethoxine is used as a broad-spectrum antimicrobial to treat or prevent infections caused by susceptible organisms. Infections treated may include pneumonia, intestinal infections (especially coccidia), soft tissue infections, and UTIs. However resistance is common, unless combined with ormetoprim. Sulfonamide antibiotic that blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase.

Interactions between Human Serum Albumin and Sulfadimethoxine

As one of the most widely used groups of antimicrobials, sulfonamides, including sulfadimethoxine (SMT), play a pivotal role in agriculture. However, recent studies have shown that sulfonamides, together with their metabolites, may pose a potential threat to human health by virtue of their accumulation in the body through the food chain. Human serum albumin (HSA), the most abundant protein in plasma, is quite versatile in function, and plays a role in maintaining the acid–base balance, regulating osmotic pressure, and catalyzing metabolic reactions. Among sulfonamides, sulfadimethoxine (SMT) plays an indispensable role and has the advantages of a wide antibacterial spectrum, stability, and ease of use. However, it is difficult to eliminate this compound from the environment.  Specifically, we used thermodynamics to determine the driving forces between SMT and HSA, followed by infrared spectroscopy to study the effect of SMT on the conformation of HSA. Lastly, the mode of binding of SMT and HSA was determined using molecular docking. The experimental results showed that sulfadimethoxine and HSA bind to site I, which was consistent with the molecular docking simulation results.[1]

In this study, we used several techniques to explore the binding mechanism between SMT and HSA. Site experiments revealed that sulfadimethoxine was bound to site I of HSA and formed a stable complex. Thermodynamic studies revealed that the stability of the complex was regulated by temperature. Results from the molecular docking study indicated that apart from van der Waals forces and hydrogen-bonding interactions, alkyl and π–σ forces played an important role in binding and conferring stability. Overall, our findings provide important biophysical insights into the potential threats of sulfadimethoxine to human health. Our experimental results were different and similar to the published studies. Through fluorescence quenching experiments, circular dichroism, synchronization, and three-dimensional fluorescence spectroscopy experiments, Ma et al. In conclusion, our experiment found that SMT could bind to HSA, and the binding not only affected the secondary structure of HSA, but also led to a decrease in the concentration of sulfadimethoxine in the blood, which provided a new direction for the study of SMT in human blood concentration.

Depression of T cell‐mediated immunity reduces sulfadimethoxine‐induced capsular inflammation

It is generally accepted that inflammation is an immune reaction not only to exogenous but also to mutated or overexpressed endogenous proteins. It has both advantages and disadvantages for humans and animals. We previously reported rapid induction of invasive follicular cell carcinomas in thickened thyroid capsules with inflammation in a rat two‐stage carcinogenesis model by treatment with the antithyroidal agent sulfadimethoxine (SDM) after single injection of the genotoxic thyroid carcinogen N‐bis(2‐hydroxypropyl)nitrosamine (DHPN). Scientists hypothesized that an unusual immunogenic response via T‐cell recognition, with respect to goiter and enhancement of inflammation by interplay between T cells and macrophages, occurs during thyroid carcinogenesis in our DHPN‐SDM rat model. This hypothesis would predict an inhibition of invasive carcinoma development under conditions whereby T cell‐mediated immunity is depressed. To clarify the association between capsular inflammation and invasive carcinoma development, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates treated with sulfadimethoxine after DHPN initiation. In addition, immunohistochemical analysis of iNOS expression in capsular lesions was carried out.[2]

The present comparative study of athymic rnu/rnu rats and euthymic rnu/+ littermates demonstrated a clear association between sulfadimethoxine‐induced thyroid capsular inflammation and invasive carcinoma development in the capsular region of rats initiated with DHPN. Although there were no significant differences in development of adenomas and intrathyroidal carcinomas between the rnu/rnu and rnu/+ groups, the multiplicity of invasive carcinomas into capsule or extrathyroidal tissue in rnu/rnu groups was significantly lower than that in the rnu/+ group indicating that their development was inhibited under the T cell‐mediated immunity‐depressed state. Although the cause of capsular inflammatory change induced by sulfadimethoxine in rnu/+ rats is not understood, thiouracil, another antithyroidal compound, is reported to induce similar changes. Therefore, the present DHPN‐sulfadimethoxine rat thyroid carcinogenesis model appears to resemble human thyroiditis cases, except for the location of the inflammation (i.e. regional capsulitis is characteristic but intrathyroidal diffuse inflammation is not evident in this model).

Sulfadimethoxine in Prevention of Turkey Coccidiosis

SULFADIMETHOXINE, N′-(2,6-dimethoxy-4-pyrimidinyl) sulfanilamide, since first synthesized by Bretschneider and Kloetzer (1955), and its antibacterial activity reported by Schnitzer et al. (1958), has stimulated a great deal of interest among the workers engaged in the field of experimental chemotherapy. In fowl, Mitrovic and Bauernfeind reported that sulfadimethoxine was therapeutically highly effective against all pathogenic species of Eimeria in chickens and turkeys. Mitrovic (1967) reported that sulfadimethoxine was also effective in therapy of fowl cholera in chickens and turkeys and infectious coryza in chickens. Since the chemoprophylactic efficacy of sulfadimethoxine in turkey coccidiosis has not as yet been investigated, the studies undertaken and completed are the object of this report.[3]

References

[1]Zhang Y, Cao Y, Li Y, Zhang X. Interactions between Human Serum Albumin and Sulfadimethoxine Determined Using Spectroscopy and Molecular Docking. Molecules. 2022 Feb 24;27(5):1526. doi: 10.3390/molecules27051526. PMID: 35268627; PMCID: PMC8911820.

[2]Imai T, Hasumura M, Cho YM, Onose J, Hirose M. Depression of T cell-mediated immunity reduces sulfadimethoxine-induced capsular inflammation and inhibits associated development of invasive thyroid follicular cell carcinomas in rats. Cancer Sci. 2007 Mar;98(3):294-8. doi: 10.1111/j.1349-7006.2007.00406.x. PMID: 17270018; PMCID: PMC11159718.

[3]Mitrovic, M. “Sulfadimethoxine in prevention of turkey coccidiosis.” Poultry science vol. 47,1 (1968): 314-9. doi:10.3382/ps.0470314