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ABBREVIATIONS

Abbreviations

AIDS: acquired immunodeficiency syndrome

CSF: cerebrospinal fluid

DHFR: dihydrofolate reductase

GI: gastrointestinal

HIV: human immunodeficiency virus

PABA: para-aminobenzoic acid

TMP: trimethoprim

SMX: sulfamethoxazole

UTI: urinary tract infection

SULFONAMIDES

HISTORICAL PERSPECTIVE

The sulfonamide drugs were the first effective chemotherapeutic agents used systemically for the prevention and cure of bacterial infections in humans. Investigations in 1932 at the I. G. Farbenindustrie in Germany resulted in the patenting of prontosil and several other azo dyes containing a sulfonamide group. Because synthetic azo dyes had been studied for their action against streptococci, Domagk tested the new compounds and observed that mice with streptococcal and other infections could be protected by prontosil. In 1933, Foerster reported giving prontosil to a 10-month-old infant with staphylococcal septicemia and achieving a dramatic cure. Favorable clinical results with prontosil and its active metabolite, sulfanilamide, in puerperal sepsis and meningococcal infections awakened the medical profession to the new field of antibacterial chemotherapy, and experimental and clinical articles soon appeared in profusion. The development of the carbonic anhydrase inhibitor–type diuretics and the sulfonylurea hypoglycemic agents followed from observations made with the sulfonamide antibiotics. For discovering the chemotherapeutic value of prontosil, Domagk was awarded the Nobel Prize in Medicine for 1938 (Lesch, 2007). The advent of penicillin and other antibiotics diminished the usefulness of the sulfonamides, but the introduction of the combination of trimethoprim (TMP) and sulfamethoxazole (SMX) in the 1970s increased the use of sulfonamides for the prophylaxis and treatment of infections.

Sulfonamides are derivatives of para-aminobenzenesulfonamide (sulfanilamide; Figure 57–1) and are congeners of para-aminobenzoic acid (PABA). Most of them are relatively insoluble in water, but their sodium salts are readily soluble. The minimal structural prerequisites for antibacterial action are all embodied in sulfanilamide itself. The sulfur must be linked directly to the benzene ring. The para-NH2 group (the N of which has been designated as N4) is essential and can be replaced only by moieties that can be converted in vivo to a free amino group. Substitutions made in the amide NH2 group (position N1) have variable effects on antibacterial activity of the molecule; substitution of heterocyclic aromatic nuclei at N1 yields highly potent compounds. The sulfone agent dapsone is discussed in Chapter 65.

Figure 57–1

Sulfanilamide and PABA. Sulfonamides are derivatives of sulfanilamide and act by virtue of being congeners of PABA. The antimicrobial and dermatological anti-inflammatory agent dapsone (4,4′-diaminodiphenyl sulfone; see Chapters 65 and 75) also bears a resemblance to PABA and sulfanilamide.

Mechanism of Action

Sulfonamides are competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of PABA into dihydropteroic acid, the immediate precursor of folic acid (Figure 57–2). Sensitive microorganisms ...

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