Sulfonamides Revisited, With an Emphasis on Dapsone

deutsche-med-wschr-1935The sulfonamide moiety is a remarkable structure giving rise to diverse drugs in arious therapeutic areas such as antibiotics, antidiabetics, diuretics and anti-inflammatory agents.

In regards to antibiotics, sulfonamides are in common use as antifungals (P. jiroveci), antiparasitics (toxoplasmosis, cyclospora, isospora, malaria) antibacterials (including against nocardia and certain ones causing STDs) and antimycobacterials (some, rapid grower NTM, leprosy).

dapsone-structure
Fig. 1: Dapsone / DADPS (diamino-diphenylsulfone

While we are all familiar with the broad activity spectrum of TMP/SMX, most of us are less so with dapsone, a sulfone with a very pretty symmetrical structure (see Figure 1). It’s development history is interesting as serendipity and astute observation were key, not modern HTS and SAR methods as described well by Barr*. Dapsone reminds us of a bit of Aspirin: a drug for which new uses are found almost every decade.dapsone

To the infectious disease clinician, the side effects of dapsone (allergy, G6PD issue, methemoglobinemia) are probably better known than its steroid-sparing anti-inflammatory properties. While there are many antibiotics for which immunomodulatory properties have been described, there are few that are being used just for this very reason.

dapsone-lapdap
Malaria treatment withdrawn due to dapsone-related AEs

As an antibiotic, dapsone’s mode of action is as an inhibitor of DHPS, just like all other sulfonamides. As an immune modulator, dapsone acts as an inhibitor of myeloperoxidase in neutrophils and eosinophils, preventing the respiratory burst. In addition, inhibition of cellular adherence to vascular endothelium and numerous effects on cytokines / lymphokines have been described. Unfortunately, as an old drug, there are many unknowns about dapsone’s effect on cellular function and signaling pathways.

The list of dermatologic conditions for which dapsone is used routinely or considered an option keeps on growing: it has been used for bullous autoimmune disorders, pemphigus, vasculitis, immune thrombopenia, SLE, hidradenitis, relapsing polychondritis, severe aphthous ulcers and more. Dermatitis herpetiformis (Duhring), an itchy skin condition associated with gluten enteropathy is often treated with dapsone or sulfapyridine.

Granuloma annulare was just recently added to the list of indications, as were Well’s disease (recurrent granulomatous dermatitis with eosinophilia) and EED (erythema elevatum diutinum). And then there are a few odd ones. How about treatment for Loxosceles reclusa (brown recluse spider) bites with dapsone? The jury is still out; as one can imagine; this is not a good topic for prospective randomized controlled studies. An older review did not show convincing evidence of efficacy for dapsone.

But wait, how about Madura foot?  Yes, this disfiguring bacterial / fungal monstrosity seen in Latin America is still an indication for dapsone treatment.  And acne too.

Historical Footnotes
In their first description of diaminodiphenylsulfone (DADPS, Dapsone) in 1908, Fromm and Wittmann already mention that the DADPS moiety could be used to develop dyeing agents for cotton. The antimicrobial activity of Prontosil rubrum, the sulfonamide dye sulfachrysoidin, was not discovered until the years 1932-1935. However, Domagk mistakenly attributed the antivicrobial activity to the chrysoidin side arm of Prontosil, not the sulfa component. It was Fourneau and Trefouel that recognized that Prontosil album (sulfanilamide) had broad antibacterial activity and it was Trefouel who – in 1937 –first described the antibacterial activity of dapsone.

* Here just a few general references on dapsone and sulfonamides:

  1.  G Wozel. Dapsone in dermatology and beyond. Arch Dermatol Res (2014) 306:103
  2. J Barr. A Short History of Dapsone, or an Alternative Model of Drug Development. J Hist Med Allied Sciences 66; 4: 425
  3. R Wolf. Dapsone. http://escholarship.org/uc/item/30m4b5kr
  4. E Fromm, J Wittmann.  Derivate des p-nitrophenols. Berichte Deutsch Chem Ges. 1908;41:2264
  5. G Domagk. Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Dtsch Med Wochenschr 1935: 250
  6. G Domagk. Eine Neue Klasse von Desinfektionsmitteln. Dtsch Med Wochenschr 1935: 829
  7. G Hobbs. Comparison of hyperbaric oxygen and dapsone therapy for loxosceles envenomation. Acad Emerg Med. 1996 Aug;3(8):758-61.

Abbreviations:

DHPS dihydropteroate synthase
NTM   non-tuberculous mycobacteria
HTS   high-throughput screening
SAR   structure-activity relationship

robert-koch-totenbett-dmw-1935
Robert Koch on his death bed – on the cover of Deutsche Medizinische Wochenschrift in 1935 (Vol 61, Nr. 21) – on the occasion of the 25th anniversary of his death May 27, 1910. There is article by Domagk in this issue on “Ene Neue Klasse von Desinfektionsmitteln”
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