Sulfonamide Antibiotics: Definition, Mechanism and Research

What are sulfonamides?

Sulfonamide (SA) antibiotics are a class of synthetic antibacterial agents, belonging to sulfonamide derivatives. The chemical structure of sulfanilamide antibiotics contains a sulfanilamide group (-SO2NH2) and an aromatic amine group (-NH2). The hydrogen on the sulfonamide group can be replaced by different heterocyclic rings to form different kinds of sulfonamides. Compared with the parent sulfanilamide, they have the advantages of high effective value, low toxicity, wide antibacterial spectrum and easy oral absorption. The free amino group on the para-position is the antibacterial active part, and if it is replaced, it loses its antibacterial effect. Amino groups must be re-released after decomposition in the body to restore activity. According to their chemical structure modification, they can be divided into the following 5 categories: (1) sulfonamide group structure modification; (2) benzene amino structure modification; (3) Simultaneous modification of sulfonamide group and benzene amino group; (4) sulfonamide compounds modified at other sites; (5) sulfonamides supramolecular complex.

Chemical structure diagram of sulfonamide.

Sulfonamides have broad-spectrum antibacterial activity and are effective against a variety of gram-positive and gram-negative bacteria. Sulfonamides have a variety of uses in medicine, including the treatment of urinary tract infections, malaria, certain skin conditions, and the prevention and treatment of infections caused by Gram-positive or Gram-negative bacteria. In addition, sulfonamides are often combined with trimethoprim to enhance their antibacterial effects, and this combination of drugs can be effective against a variety of bacterial infections.

Mechanism of action of sulfonamides

Bacteria can not directly use folic acid in its growth environment, but use p-aminobenzoic acid (PABA) in the environment, dihydrotretin, glutamate in the dihydrofolate synthase catalyzed in bacteria to synthesize dihydrofolate. Dihydrofolate forms tetrahydrofolate under the action of dihydrofolate reductase. Tetrahydrofolate, as a coenzyme of one carbon unit transferase, is involved in the synthesis of nucleic acid precursors (purine, pyrimidine). Nucleic acids are essential components of bacterial growth and reproduction. The chemical structure of sulfanilamide is similar to PABA, and it can compete with PABA for dihydrofolate synthetase, which affects the synthesis of dihydrofolate, and thus inhibits the growth and reproduction of bacteria. Because sulfanilamide can only inhibit bacteria but not bactericidal effect, the elimination of pathogens in the body ultimately depends on the body's defense ability.

Resistance to sulfonamides

After repeated contact with the drug, the sensitivity of the bacteria to the drug decreases or even disappears. Bacteria are prone to develop resistance to sulfonamides, especially when the dosage or course of treatment is insufficient. The reason for the development of resistance may be that the bacteria change the metabolic pathway, such as producing more dihydrofolate synthetase, or can directly use folate in the environment, and the intestinal flora often spreads through the transfer of R factor. When combined with antibacterial synergists, it can reduce or delay the occurrence of resistance. Bacteria have cross-resistance to various types of sulfanilamide drugs, that is, after bacteria become resistant to one sulfanilamide drug, they are also ineffective to another sulfanilamide drug. However, there was no cross-resistance with other antimicrobial agents. Absorption, distribution, metabolism, excretion Because the role of sulfonamides is antibacterial rather than bactericidal, to ensure the antibacterial effect of sulfonamides, it is necessary to maintain an effective blood concentration for a long enough period of time.

Sulfonamide antibiotics list

There are more than 40 sulfonamides used for bacterial infections in humans and animals, among which drugs such as sulfadiazine, sulfadimethoxil, sulfaquinoxaline, sulfamethoxazole, sulfachlorazine and sulfathiazole are the most common.

Sulfamethoxazole: Often used in combination with trimethoprim to form a compound preparation such as Bactrim (Septra).

Sulfisoxazole: A short-acting sulfanilamide drug commonly used in the treatment of acute urinary tract infections.

Sulfadiazine: Has a long half-life and can be used in the prevention and treatment of malaria.

Sulfamethopyrazone: Also a long-acting sulfamide, used in the prevention and treatment of malaria.

Silver sulfadiazine: Mainly used for infection prevention of burn wounds.

Sulfathiazole: A short-acting sulfanilamide drug used to treat certain bacterial infections.

Sulfacetamide sodium: It is mainly used in the treatment of eye infections.

Sulfadimidine: Used to treat certain bacterial infections, such as respiratory infections.

Sulfonamide antibiotics at BOC Sciences

Research progress of sulfonamide

Potential toxicological effects of sulfonamides antibiotics

Sulfamethodiazine (SMR) and sulfamethoxazole (SMT) are commonly used veterinary antibiotics, two sulfonamides that have been frequently detected in the environment in recent years. Inappropriate intake of SMT and SMR can lead to goiter and hypothyroidism, central nervous system toxicity, and liver and kidney damage, among other harms. Therefore, it is important to study the direct harm of SA to organisms.

Zhu et al. studied the toxicological mechanisms of SMR and SMT by molecular docking, DFT and multispectral techniques, using human and bovine serum albumin (HSA and BSA) as model proteins. The quenching effect of SMR on HSA/BSA endogenous fluorescence is higher than that of SMT, which is due to the stronger binding effect of pyrimidine ring on HSA/BSA than oxazole ring. The binding of SAs and HSA/BSA is mainly achieved through hydrogen bonding and hydrophobic interaction, and this concept is also supported by molecular models. The α helix content of HSA/BSA induced by SMR/SMT was reduced, indicating that the α helix structure of HSA/BSA protein had greater extensibility. These results could provide useful toxicological information on the hazards of SAs in response to the growing concern that SAs may pose a toxic threat to organisms.

Biosensors simultaneously detect multiple sulfonamides

Unreasonable use, abuse, or cross use of sulfonamides (SAs) in animal husbandry will lead to the residual of SAs in the environment (such as water), which will adversely affect the ecosystem, bacterial resistance, and human health. Therefore, it is very necessary to develop simple, fast and simultaneous detection of multiple SAs detection methods to achieve rapid screening of total SAs residues in environmental water.

Liu et al. reported a biosensor based on mixed screening of multiple sulfonamides to generate broad-spectrum specific nucleic acid aptamers. They screened aptamers targeting a mixture of three SAs antibiotics and obtained three aptamers with different specificity. One of them had a similar binding force to all six SAs drugs tested, with Kd values ranging from 0.22 to 0.63 μM. For the other two aptamers, one specifically recognizes SQX and the other specifically recognizes SDM and SCZ. The established label-free aptamer sensor can be successfully applied to the detection of real samples, and the LOD range of six SAs drugs in lake water samples is 0.14-0.71μM. The multi-target SELEX strategy provides a shortcut for generating broad-spectrum aptamers for detecting antibiotic families. At the same time, based on the reliability of the aptamer sensor to detect real samples, the aptamer is likely to be used to establish other sensor platforms to detect SAs antibiotics.

References

1. Zhu, M., et al. Potential toxic effects of sulfonamides antibiotics: Molecular modeling, multiple-spectroscopy techniques and density functional theory calculations. Ecotoxicology and Environmental Safety. 2022, 243: 113979.
2. Li, X., et al. Multiplexed SELEX for sulfonamide antibiotics yielding a group-specific DNA aptamer for biosensors. Analytical Chemistry. 2023, 95(44): 16366-16373.