Antimicrobial Drugs

Sulfa Drugs

Antibacterial spectrum - Range of activity of an antimicrobial against

bacteria. A broad-spectrum antibacterial drug can inhibit a wide variety of
gram-positive and gram-negative bacteria, whereas a narrow-spectrum drug
is active only against a limited variety of bacteria.
Bacteriostatic activity - The level of antimicrobial activity that inhibits the
growth of an organism. This is determined in vitro by testing a standardized
concentration of organisms against a series of antimicrobial dilutions. The
lowest concentration that inhibits the growth of the organism is referred to as
the minimum inhibitory concentration (MIC).
Bactericidal activity - The level of antimicrobial activity that kills the test
organism. This is determined in vitro by exposing a standardized
concentration of organisms to a series of antimicrobial dilutions. The lowest
concentration that kills 99.9% of the population is referred to as the minimum
bactericidal concentration (MBC).
LD50 - The value of LD50 for a substance is the dose required to kill half the
members of a tested population after a specified test duration.

Bactericidal vs. Bacteriostatic

Ehrlichs Magic Bullets

Selective toxicity: A drug that kills harmful microbes without
damaging the host

Dr Paul Ehrlich &

Dr Hata Sahachiro

Paul Ehrlich (1854 1915), Nobel Prize for

Medicine in 1908

Fleming and Penicillin

Alexander Fleming (1881 1955), Nobel Prize in Medicine (1945)

Sulfa Drugs, History/Discovery

Discovered by Gerhard Domagk (1895-1964), a
German biochemist
In 1932, tested a dye, Prontosil
Although it had no antibacterial properties, a
slight change in its chemical make-up resulted in
anti-bacterial activity against streptococci in
mice
Derivatives based on the Prontosil sulfonamide
group were developed, resulting in so-called
sulfa drugs
Sulfa drugs revolutionized medicine and saved
many thousands of lives

Sulfa Drugs in World War II

The discovery of Sulfanilamide greatly
affected the mortality rate during World
War II.
American soldiers were taught to
immediately sprinkle sulfa powder on any
open wound to prevent infection.
Every soldier was issued a first aid pouch
that was designed to be attached to the
soldiers waist belt.
The first aid pouch contained a package
of sulfa powder and a bandage to dress the
wound.
One of the main components carried by a
combat medic during World War II was
sulfa powder and sulfa tablets.

Sulfanilamide
Prontosil

Prontosil was the parent

drug of sulfonamide family,
first used in 1936
4-[(2,4-diaminophenyl)azo]benzenesulfonamide

Sulfanilamide and its

derivatives were the first
successful antibacterial drug
discovered.

Sulfanilamide

4-aminobenzenesulfonamide

Diseases that were once fatal now had an cheap, available treatment.
Mortality rates dropped significantly for diseases like pneumonia and
meningitis.

Chemical structures
PABA (para-aminobenzoic acid)
has a similar structure to the
sulfonamide base structure.
PABA is used naturally within the
bacterial cell as an intermediate in
the synthesis of folic acid.
The R1 and R4 groups indicated on
the sulfonamide base structure
differ between sulfa drugs.

FOLIC ACID

Mechanism of Action
DIHYDROPTEROATE
SYNTHASE

PABA

FOLIC ACID
REDUCTASE

Folic Acid

Dihydrofolic
Acid

Trimethoprim
DIHYDROFOLIC
ACID REDUCTASE

Sulfonamides

DNA
synthesis

Folinic
Acid

Tetrahydrofolic
Acid
FORMYL
GROUP
TRANSFER

Folic
Acid
Dihydrofolic
Acid
Tetrahydrofolic
Acid

Folinic
Acid

Mechanism of Action
All cells require folic acid for growth (nucleic acid and protein synthesis).
Folic acid diffuses or is transported into human cells.
Folic acid cannot cross bacterial cell walls by diffusion or active transport.
For this reason bacteria must synthesize folic acid from PABA which can freely
diffuse into the cell.
PABA is converted to folic acid via the enzyme dihydropteroate synthase.
Sulfonamides act at this step by competitively inhibiting the incorporation of
PABA into folic acid.
Folic acid, therefore is not produced by and is unavailable for bacterial DNA
synthesis.

Microbial
Sources of
Antibiotics

Mechanisms of Antimicrobial Action

Bacteria have their own enzymes for
Cell wall formation
Protein synthesis
DNA replication
RNA synthesis
Synthesis of essential metabolites
Viruses use host enzymes inside host cells
Fungi and protozoa have own enzymes
The more similar the pathogen and host enzymes, the
more side effects the antimicrobials will have

Modes of Antimicrobial Action

Competitive Inhibitors
Sulfonamides (Sulfa drugs)
Inhibit folic acid synthesis
Broad spectrum