Chemical Medicine

Antimicrobial Drugs,Sulfa Drugs

Ehrlich’s Magic Bullets

Paul Ehrlich(1854 –1915), Nobel Prize for Medicine in 1908, Salvarsan and 606Dr Paul Ehrlich &

Dr Hata Sahachiro

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

Fleming and Penicillin

Alexander Fleming(1881 –1955), Nobel Prize in Physiology or 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

http://nobelprize.org/nobel_prizes/medicine/laureates/1939/domagk.jpg

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.

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

PABA Folic Acid

Dihydrofolic Acid

Tetrahydrofolic AcidFolinic

AcidDNA synthesis

DIHYDROPTEROATE SYNTHASE

Folic Acid reductase

Dihydrofolic acid reductase

FORMYL GROUP TRANSFER

Sulfonamides

Trimethoprim

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

• Penicillin (over 50 compounds)– Share 4-sided ring ( lactam ring)

• Natural penicillins• Narrow range of action• Susceptible to penicillinase ( lactamase)

Antibacterial Antibiotics Inhibitors of Cell Wall

Synthesis

Prokaryotic Cell Walls

Penicillins

Penicillinase ( Lactamase)

• Penicilinase-resistant penicillins• Carbapenems: very broad spectrum• Monobactam: Gram negative

• Extended-spectrum penicillins• Penicillins + -lactamase inhibitors

Semisynthetic Penicillins

• 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

Other Inhibitors of Cell Wall Synthesis

• Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation– Isoniazid

(INH)–Ethambutol

• 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)

Inhibitors of Protein Synthesis

• Polymyxin B (Gram negatives)– Topical– Combined with bacitracin and neomycin

(broad spectrum) in over-the-counter preparation

Injury to the Plasma Membrane

• Rifamycin– Inhibits RNA synthesis– Antituberculosis

• Quinolones and fluoroquinolones– Ciprofloxacin– Inhibits DNA gyrase– Urinary tract infections

Inhibitors of Nucleic Acid Synthesis

– Sulfonamides (Sulfa drugs)• Inhibit folic acid synthesis• Broad spectrum

Competitive Inhibitors

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 DrugsNucleoside and Nucleotide Analogs

Analogs Block DNA Synthesis

• Inhibit assembly– Indinavir (HIV)

• Inhibit attachment– Zanamivir (Influenza)

• Inhibit uncoating– Amantadine (Influenza)

Antiviral DrugsEnzyme Inhibitors

• Interferons prevent spread of viruses to new cells (Viral hepatitis)

• Natural products of the immune system in viral infections

Antiviral DrugsEnzyme Inhibitors

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

• Prevent ATP generation (Tapeworms)• Alters membrane permeability

(Flatworms)• Neuromuscular block (Intestinal

roundworms)• Inhibits nutrient absorption (Intestinal

roundworms)• Paralyzes worm (Intestinal

roundworms)

Antihelminthic Drugs

• 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

The Future of Chemotherapeutic Agents

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).