Download Antimicrobial Drugs

Chemical Medicine
Antimicrobial Drugs,
Sulfa Drugs
Ehrlich’s 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, Salvarsan and 606
Fleming and Penicillin
Alexander Fleming(1881 –1955), Nobel Prize in Physiology or Medicine (1945)
Sulfa Drugs, History/Discovery
http://nobelprize.org/nobel_
prizes/medicine/laureates/19
39/domagk.jpg
• 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 Sulfa
nilamide greatly affect
ed the mortality rate
during World War II.
• American soldiers
were taught to
immediately sprinkle
sulfa powder on any
open wound to
prevent infection.
http://home.att.net
Sulfanilamide
• Grandparent of
sulfonamide family of
drugs first used in
1936
• Sulfanilamide and its
derivatives were said
to have “dethroned
the captain of the
men of death”
Prontosil
4-[(2,4-diaminophenyl)azo]benzenesulfonamide
Sulfanilamide
4-aminobenzenesulfonamide
Chemical structures
FOLIC ACID
Mechanism of Action
DIHYDROPTEROATE
SYNTHASE
PABA
Folic Acid reductase
Dihydrofolic
Acid
Folic Acid
Trimethoprim
Dihydrofolic acid
reductase
Sulfonamides
DNA
synthesis
FORMYL
GROUP
TRANSFER
Folinic
Acid
Tetrahydrofolic
Acid
Microbial
Sources of
Antibiotics
Antibiotic Spectrum of Activity
• No antibiotic is effective against all microbes
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 eukaryotic enzymes
• The more similar the pathogen and host enzymes,
the more side effects the antimicrobials will have
Modes of Antimicrobial
Action
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Penicillin (over 50 compounds)
– Share 4-sided ring (b lactam ring)
• Natural penicillins
• Narrow range of action
• Susceptible to penicillinase (b lactamase)
Prokaryotic Cell Walls
Penicillins
Penicillinase (b Lactamase)
Semisynthetic Penicillins
• Penicilinase-resistant penicillins
• Carbapenems: very broad spectrum
• Monobactam: Gram negative
• Extended-spectrum penicillins
• Penicillins + b-lactamase inhibitors
Other Inhibitors of Cell Wall
Synthesis
• Cephalosporins
– 2nd, 3rd, and 4th
generations more
effective against
gram-negatives
Other Inhibitors of Cell Wall
Synthesis
• Polypeptide antibiotics
– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin
• Glycopeptide
• Important "last line" against antibiotic resistant S.
aureus
Other Inhibitors of Cell Wall
Synthesis
• Antibiotics
effective against
Mycobacteria:
interfere with
mycolic acid
synthesis or
incorporation
– Isoniazid (INH)
– Ethambutol
Inhibitors of Protein Synthesis
• Broad spectrum, toxicity problems
• Examples
– Chloramphenicol (bone marrow)
– Aminoglycosides: Streptomycin,
neomycin, gentamycin (hearing, kidneys)
– Tetracyclines (Rickettsias & Chlamydia;
GI tract)
– Macrolides: Erythromycin (gram +, used
in children)
Injury to the Plasma Membrane
• Polymyxin B (Gram negatives)
– Topical
– Combined with bacitracin and neomycin
(broad spectrum) in over-the-counter
preparation
Inhibitors of Nucleic Acid
Synthesis
• Rifamycin
– Inhibits RNA synthesis
– Antituberculosis
• Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase
– Urinary tract infections
Competitive Inhibitors
– Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Antifungal Drugs
• Fungi are
eukaryotes
• Have unique
sterols in their
cell walls
• Pathogenic fungi
are often outside
the body
Antiviral Drugs
• Viruses are composed of nucleic acid,
protein capsid, and host membrane
containing virus proteins
• Viruses live inside host cells and use
many host enzymes
• Some viruses have unique enzymes for
DNA/RNA synthesis or protein cutting
in virus assembly
Antiviral Drugs
Nucleoside and Nucleotide Analogs
Analogs Block DNA Synthesis
Antiviral Drugs
Enzyme Inhibitors
• Inhibit assembly
– Indinavir (HIV)
• Inhibit attachment
– Zanamivir (Influenza)
• Inhibit uncoating
– Amantadine (Influenza)
Antiviral Drugs
Enzyme Inhibitors
• Interferons prevent spread of viruses to
new cells (Viral hepatitis)
• Natural products of the immune system
in viral infections
Antiprotozoan Drugs
• Protozoa are
eukaryotic cells
• Many drugs are
experimental and
their mode of
action is
unknown
Antihelminthic Drugs
• Helminths are
macroscopic
multicellular eukaryotic
organisms: tapeworms,
roundworms,
pinworms, hookworms
Antihelminthic Drugs
• Prevent ATP generation (Tapeworms)
• Alters membrane permeability (Flatworms)
• Neuromuscular block (Intestinal
roundworms)
• Inhibits nutrient absorption (Intestinal
roundworms)
• Paralyzes worm (Intestinal roundworms)
The Future of
Chemotherapeutic Agents
• Antimicrobial peptides
– Broad spectrum antibiotics from plants and
animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)
• Antisense agents
– Complementary DNA or peptide nucleic acids
that binds to a pathogen's virulence gene(s)
and prevents transcription
References
•
•
•
•
Gray, J., Therapeutic Choices, Canadian Pharmacists
Association, 2007 (1112, 1448)
Steinert, D. History of WWII Medicine, World War II
Combat Medic (http://home.att.net/~steinert/wwii.htm)
Ophardt, C. “Antibacterial Agents, Sulfa Drugs”, Virtual
Chembook
(http://www.elmhurst.edu/~chm/vchembook/653sulfa.html)
Dharmananda, S., Differentiating Sulfur Compounds:
Sulfa Drugs, Glucosamine Sulfate, Sulfur, and Sulfiting
Agents. Institute for Traditional Medicine.
(http://www.itmonline.org/arts/sulfa.html).