O Antibacterial Sulfonamides

Chemo Secrets From a Breast Cancer Survivor

Breast Cancer Survivors

Get Instant Access

The sulfonamide antimicrobial drugs were the first effective chemotherapeutic agents that could be used systemically for the cure of bacterial infections in humans. Their introduction led to a sharp decline in the morbidity and mortality of infectious diseases. The rapid development of widespread resistance to the sulfonamides soon after their introduction and the increasing use of the broader-spectrum penicillins in the treatment of infectious disease diminished the usefulness of sulfonamides. Today, they occupy a rather small place in the list of therapeutic agents that can be used for infectious disease. They are not completely outmoded, however. In the mid-1970s, the development of a combination of trimethoprim and sulfamethoxazole and the demonstration of its usefulness in the treatment and prophylaxis of certain opportunistic microbial infections led to resurgence in the use of some sulfonamides.

Fritz Mietzsch and Joseph Klarer of the I. G. Farbenindustrie laboratories systematically synthesized a series of azo dyes, each containing the sulfonamide functional group, as potential antimicrobial agents. Sulfonamide azo dyes were included in the test series because they were readily synthesized and possessed superior staining properties. The Bayer pathologist-bacteriologist who evaluated the new Mietzsch-Klarer dyes was a physician named Gerhard Domagk.100-102 In 1932, Domagk began to study a brilliant red dye, later named Prontosil. Prontosil was found to protect against, and cure, streptococcal infections in mice.100 Interestingly, Prontosil was inactive on bacterial cultures. Domagk and others continued to study Prontosil, and in 1933, the first of many cures of severe bacterial infections in humans was reported by Foerster,103 who treated a 10-month-old infant suffering from staphylococcal septicemia and obtained a dramatic cure. The credit for most of the discoveries relating to Prontosil belongs to Domagk, and for his pioneering work in chemotherapy he was awarded the Nobel Prize in medicine and physiology in 1938. The Gestapo prevented him from actually accepting the award, but after the war, he received it in Stockholm in 1947.

Prontosil is totally inactive in vitro but possesses excellent activity in vivo. This property of the drug attracted much attention and stimulated a large body of research activity into the sulfonamides. In 1935, Trefouel and coinvestigators104 performed a structure-activity study on the sulfonamide azo dyes and concluded that the azo linkage was reductively cleaved to release the active antibacterial product, sulfanilamide. This finding was confirmed in 1937 when Fuller105 isolated free sulfanilamide from the blood and urine of patients being treated with Prontosil. Favorable clinical results were reported with Prontosil and the active metabolite itself, sulfanilamide, in puerperal sepsis and meningococcal infections. All of these findings ushered in the modern era of chemotherapy and the concept of the prodrug.

Following the dramatic success of Prontosil, a host of sulfanilamide derivatives was synthesized and tested. By 1948, more than 4,500 compounds106 had been evaluated. Of these, only about two dozen have been used in clinical practice. In the late 1940s, broader experience with sulfon-amides had begun to demonstrate toxicity in some patients, and resistance problems brought about by indiscriminate use of sulfonamides limited their use throughout the world. The penicillins were excellent alternatives to the sulfonamides, and they largely replaced the latter in antimicrobial chemotherapy.

Today, there are a few sulfonamides (Table 6.7) and especially sulfonamide-trimethoprim combinations that are used extensively for opportunistic infections in patients with AIDS.107 A primary infection that is treated with the combination is PCP. The sulfonamide-trimethoprim combination can be used for treatment and prophylaxis. Additionally, cerebral toxoplasmosis can be treated in active infection or prophylactically. Urinary tract infections and burn ther-apy107-111 round out the list of therapeutic applications. The sulfonamides are drugs of choice for a few other types of infections, but their use is quite limited in modern antimicrobial chemotherapy.107-111

The sulfonamides can be grouped into three classes on the basis of their use: oral absorbable agents, designed to give systemic distribution; oral nonabsorbable agents such as sulfasalazine; and topical agents such as sodium sulfacetamide ophthalmic drops.

TABLE 6.7 Therapy with Sulfonamide Antibacterials

Disease/Infection Sulfonamides Commonly Used

TABLE 6.7 Therapy with Sulfonamide Antibacterials

Disease/Infection Sulfonamides Commonly Used

Relatively Common Use

Treatment and prophylaxis of Pneumocystis carinii pneumonia Treatment and prophylaxis of cerebral toxoplasmosis First attack of urinary tract infection

Burn therapy: prevention and treatment of bacterial infection Conjunctivitis and related superficial ocular infections Chloroquine-resistant malaria (Chapter 9)

Less Common Infections/Diseases

Trimethoprim-sulfamethoxazole Pyrimethamine-sulfadiazine Trimethoprim-sulfamethoxazole Silver sulfadiazine and mafenide Sodium sulfacetamide Combinations with quinine, others Sulfadoxine Sulfalene

Drugs of Choice or Alternates

Nocardiosis

Severe traveler's diarrhea Meningococcal infections

Generally Not Useful

Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxasole

Sulfonamides, only if proved to be sulfonamide sensitive; otherwise, penicillin G, ampicillin, or (for penicillin-allergic patients) chloramphenicol should be used

Streptococcal infections

Prophylaxis of recurrent rheumatic fever

Other bacterial infections

Vaginal infections Reduction of bowel flora Ulcerative colitis

Most are resistant to sulfonamides Most are resistant to sulfonamides

The low cost of penicillin and the widespread resistance to sulfonamides limit their use; sulfonamides are still used in a few countries The FDA and USP-DI find no evidence of efficacy Effectiveness not established Corticosteroid therapy often preferred Relapses common with sulfonamides Salicylazosulfapyridine

Side effects of the sulfanilamides sometimes mimic ulcerative colitis

Nomenclature of the Sulfonamides

Sulfonamide is a generic term that denotes three different cases:

1. Antibacterial s that are aniline-substituted sulfonamides (the "sulfanilamides").

2. Prodrugs that react to generate active sulfanilamides (i.e., sulfasalazine).

3. Nonaniline sulfonamides (i.e., mafenide acetate).

There are also other commonly used drugs that are sul-fonamides or sulfanilamides. Among these are the oral hypoglycemic drug tolbutamide, the diuretic furosemide, and the diuretic chlorthalidone.

In pharmaceutical chemistry, pKb values are not used to compare compounds that are Lewis bases. Instead, if a pKa of an amine is given, it refers to its salt acting as the conjugate acid. For example, aniline with a pKa of 4.6 refers to

It does not refer to

A negative charge on a nitrogen atom is typically not stable unless it can be delocalized by resonance. This is what happens with the sulfanilamides. Therefore, the single pKa usually given for sulfanilamides refers to the loss of an amide proton (Fig. 6.8)

Mechanism of Action of the Sulfonamides

Folinic acid (N5-formyltetrahydrofolic acid), N5,N10-methyl-enetetrahydrofolic acid, and N10-formyltetrahydrofolic acid are intermediates of several biosynthetic pathways that compose the one-carbon pool in animals, bacteria, and plants. A key reaction involving folate coenzymes is catalyzed by the enzyme thymidylate synthase, which transfers a methyl group from N5,N10-tetrahydrofolic acid to deoxyuridine monophosphate to form deoxythymidine monophosphate, an important precursor to DNA (Fig. 6.9).

Another key reaction is the generation of formyl groups for the biosynthesis of formylmethionyl tRNA units, the primary building blocks in protein synthesis. The sulfonamides are structural analogs of PABA that competitively inhibit the action of dihydropteroate synthase, preventing the addition of PABA to pteridine diphosphate and blocking the net biosynthesis of folate coenzymes. This action arrests bacterial growth and cell division. The competitive nature of the sulfonamides' action means that the drugs do no permanent damage to a microorganism; hence, they are bacteriostatic. The sulfonamides must be maintained at a minimum effective concentration to arrest the growth of bacteria long enough for the host's immune system to eradicate them.

Folate coenzymes are biosynthesized from dietary folic acid in humans and other animals. Bacteria and protozoa must biosynthesize them from PABA and pteridine diphosphate. Microbes cannot assimilate folic acid from the growth medium or from the host. The reasons for this are poorly understood,102 but one possibility is that bacterial cell walls may be impermeable to folic acid.

Trimethoprim is an inhibitor of dihydrofolate reductase, which is necessary to convert dihydrofolic acid (FAH2) into tetrahydrofolic acid (FAH4) in bacteria (Fig. 6.10). Anand has reviewed this biochemistry.102 Trimethoprim does not have a h,c-s-n

General Sulfonamide Structure

HoNL

Aniline

Sulfanilamide

Was this article helpful?

0 0
How To Reduce Acne Scarring

How To Reduce Acne Scarring

Acne is a name that is famous in its own right, but for all of the wrong reasons. Most teenagers know, and dread, the very word, as it so prevalently wrecks havoc on their faces throughout their adolescent years.

Get My Free Ebook


Responses

  • steven
    Why protonsil is inactive in it vitro study?
    3 years ago

Post a comment