Pharmaceutical Microbiology

Sulfonamide & mechanism of action

Written by MicroDok

Sulfonamide or sulpha drugs are generally known as folate synthesis inhibitors because they inhibit the synthesis of folic acid, an important precursor for the synthesis of nucleic acids in pathogenic bacteria. They are antimetabolites; and antibiotics in this category include pyrimethamine, trimethoprim, sulphamethoxazole and sulphamethoxazole-trimethoprim. Sulfonamide are the largest antibiotic family that acts as antimetabolites; and they have activity against a wide variety of pathogenic bacteria. Antibiotics that are antimetabolites are growth factor analogues because they competitively fight for growth precursors (e.g. folic acid) in the target organism, and thus inhibit or disrupt cell division in bacteria. By inhibiting a key step in the synthesis of folic acid (an important precursor for the biosynthesis of bacterial DNA and RNA), the Sulfonamide are generally known as nucleic acid synthesis inhibitors.          


Sulfonamide are synthetic antibacterial agents; and they are generally produced by chemical modifications of sulphanilamide (originally known as prontosil). They are not synthesized by microorganisms as is the case for the other groups of antibacterial agents.


The basic structure of the Sulfonamide is sulphanilamide (Figure 1A), and sulphanilamide is a structural analogue of Para-Aminobenzoic Acid, PABA (Figure 1B). Chemical modification of sulphanilamide by synthetic processes produces additional Sulfonamide.

Figure 1: General structure of sulphanilamide (A) and PABA (B). Sulfonamide are structural analogues of PABA; and they compete for the enzyme (dihydropteroate synthetase) that catalyzes the conversion of PABA to dihydropteroate, required for the synthesis of folic acid in bacteria. Folic acid or folate is required for the synthesis of nucleic acids in bacteria, and their inhibition interferes with the overall cell development.


The Sulfonamide are clinically used for a variety of infections caused by pathogenic bacteria especially urinary tract infections (UTIs). They are also clinically effective for treating bacterial endocarditis, otitis media, lower respiratory tract infections, rheumatic fever, chlamydial infections and nocardiosis. Sulfonamide are also used to treat some non-bacterial infections especially those caused by pathogenic protozoa. A combination of sulphamethoxazole-trimethoprim have a broader spectrum of activity than any of the antibiotic used alone; and they are very effective for treating some infections caused by both Gram positive and some Gram negative rods especially in cases where resistance arises for Sulfonamide.    


Sulfonamide broad spectrum antibiotics and are active against pathogenic Gram positive and some Gram negative bacteria. They are bacteriostatic in action but some antimetabolites are bacteriocidal.


Sulfonamide are folate inhibitors. They compete for PABA, an important precursor required for the synthesis of folate or folic acid bacteria. Pathogenic bacteria are inefficient to synthesize folate or folic acid; and thus they derive their folic acid from PABA (a structural analogue of the Sulfonamide). Humans derive their folic acid from their daily dietary intake, and this makes the Sulfonamide to be selectively toxic in action. PABA is structurally synonymous to Sulfonamide; and thus the antibiotic enters into reaction with PABA and competes for the active site of dihydropteroate synthetase, an important enzyme that catalyzes the combination of PABA with other precursors in the early stages of folic acid synthesis in bacteria.

Once the utilization of PABA is competitively inhibited by Sulfonamide; the antibiotic becomes incorporated into the metabolic pathway for folate synthesis, and this interferes with the biosynthesis of nucleic acids (DNA and RNA) in the bacteria. DNA and RNA direct cell division in bacteria; and when their synthesis is compromised (especially in the presence of antimetabolites such as the Sulfonamide), bacterial growth will be inhibited and death of the pathogen may ensue. Sulphamethoxazole-trimethoprim has enhanced antibacterial activity than the earlier Sulfonamide because they act at on the metabolic pathway for folate synthesis at a point after the Sulfonamide; and they specifically interfere with the activity of dihydrofolate reductase, an enzyme that converts folic acid to its reduced form required by bacteria. Sulfonamides do not interfere with the metabolism of mammalian cell because humans do not synthesize folate or folic acid.


The clinical efficacy of the Sulfonamide is compromised by the development of resistance in some pathogenic bacteria. Pathogenic bacteria that do not utilize extracellular folic acid but synthesize their own folate are resistant to Sulfonamide. Bacterial resistance to Sulfonamide when used alone has necessitated the need to use sulphamethoxazole-trimethoprim which produces better clinical outcome than when each of the antibiotics is used alone.


Sulfonamide are well absorbed by the body when administered orally; and they are excreted in urine.


The Sulfonamide rarely have untoward effects. However, side effects may include mild skin rashes, fever and gastrointestinal disturbances. Some patients develop hypersensitivity after the oral administration of Sulfonamide.


Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Drusano G.L (2007).  Pharmacokinetics   and   pharmacodynamics   of   antimicrobials.  Clin   Infect   Dis, 45(suppl):89–95.

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India.

Axelsen P. H (2002). Essentials of Antimicrobial Pharmacology. Humana Press, Totowa, NJ.

Murray P.R, Baron E.J, Jorgensen J.H., Pfaller M.A and Yolken R.H (2003). Manual of Clinical Microbiology. 8th edition. Volume 2. American Society of Microbiology (ASM) Press, Washington, D.C, U.S.A.

Murray P.R, Baron E.J, Jorgensen J.H., Pfaller M.A and Yolken R.H (2003). Manual of Clinical Microbiology. 8th edition. Volume 1. American Society of Microbiology (ASM) Press, Washington, D.C, U.S.A.

Murray P.R., Rosenthal K.S., Kobayashi G.S., Pfaller M. A. (2002). Medical Microbiology. 4th edition. Mosby Publishers, Chile.

Prescott L.M., Harley J.P and Klein D.A (2005). Microbiology. 6th ed. McGraw Hill Publishers, USA.

Mandell G.L., Bennett J.E and Dolin R (2000). Principles and practice of infectious diseases, 5th edition. New York: Churchill Livingstone.

Katzung, B. G.  (2003). Basic and Clinical Pharmacology (9th ed.). NY, US, Lange.

Hardman JG, Limbird LE, eds.  Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.


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