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Pharmacology and development of Antibiotics (Penicillin) and Antiseptics13/02/13By:Mohit Kumar SharmaPhD Final year

Eukaryotic cell

Prokaryotic cellCell types

Bacterial classification based on Gram staining

Gram staining technique

Gram positiveGram negativeBacterial classification based on Gram staining

Peptidoglycan

Transpeptidase cross-linking to peptidoglycan sheets

Few Examples of different classes of Bacteria

- Skin- Tears- Saliva- Stomach acid

Protection against bacteriaSkin The skin is tough, dry, salty, oily, rich in fatty acids and urea, low in nutrients (lots of dead, empty cells) & thick. The sweat glands secrete a mixture of salt & fatty acids that inhibit many microbes.

TearsLysozyme is an enzyme, present in tears that LYSES many prokaryotic cells by digesting the peptidoglycan in their cell walls.

-Through hydrolysis of glycosidic linkages.

SalivaThere is a continuous flow of fluid (saliva) through the mouth which FLUSHES loose microbes into the stomach.

Stomach acidThe stomach contains a strong (hydrochloric) acid. Many microbes are killed by this acidic environment and digested by the proteolytic enzymes in the digestive system.

What are Antibiotics?- Antibiotics, also known as antibacterials, are types of medications that destroy or slow down the growth of bacteria.

- The term antibiotic was first used in 1942 by Selman Waksman

The Greek word anti means "against", and bios means "life" (bacteria are life forms).

- Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 atomic mass units

- The first antibiotic was penicillin.

- Penicillin-related antibiotics such as ampicillin, amoxicillin and benzylpenicilllin are widely used today to treat a variety of infections.How do antibiotics work?

Although there are a number of different types of antibiotic they all work in one of two ways:

- A bactericidal antibiotic kills the bacteria. Penicillin is a bactericidal. A bactericidal usually either interferes with the formation of the bacterium's cell wall or its cell contents.

- A bacteriostatic stops bacteria from multiplying.Targets of Antimicrobials

1. Cell wall inhibitorsBlock synthesis and repairPenicillinsCephalosporinsCarbapenemsVancomycinBacitracinFosfomycinIsoniazid2. Cell membraneCauselossofselective permeabilityPolymyxinsDaptomycin3. DNA/RNAInhibit replication and transcriptionInhibit gyrase(unwinding enzyme) QuinolonesInhibit RNA polymerase RifampinRibosomemRNADNA4. Protein synthes is inhibitors acting on ribosomesSite of action50S subunitErythromycinClindamycinSynercidPleuromutilinsSite of action30S subunitAminoglycosides Gentamicin StreptomycinTetracyclinesGlycylcyclinesBoth 30Sand 50SBlocks initiation of proteinsynthesis Linezolid5. Folic acid synthesisBlock pathways and inhibitmetabolism Sulfonamides (sulfa drugs) TrimethoprimSubstrateEnzymeProductMechanisms of Drug ActionInhibition of cell wall synthesisInhibition of nucleic acid structure and functionInhibition of protein synthesisInterference with cell membrane structure or functionInhibition of folic acid synthesisPenicillin

Alexander Fleming- 1928, Alexander Fleming - Observed antibiosis against bacteria by a fungus of the genus Penicillium. - 1940, Florey and Chain - Began work on isolating and synthezing large amounts of Penicillin.- 1940, Preclinical trials in mice- 1941, Phase II Clinical trial- 1944 - Used in WWII to treat infections- Late 1940s - available for general use in US

History of PenicillinIn 1928, while working on influenza virus, he observed that mould had developed accidently on a staphylococcus culture plate and that the mould had created a bacteria-free circle around itself. He was inspired to further experiment and he found that a mould culture prevented growth of staphylococci, even when diluted 800 times. He named the active substance penicillin.

Phase 2- seriously ill policeman- Staph and streph septocemia, abcesses, discharging sinusesInjected with penicillin every 3 hrsUrine collected and unmetabolised penicillin extracted and reused!!Patient recovered after 5 daysFirst demonstration of effectiveness of penicillin systemically in humansHad previously been used to treat eye infections by Paine 10yrs previously (topical application)23

Staphylococcusaureus(bacterium)Penicilliumchrysogenum(fungus)Zone wherebacterial growthis inhibitedAntibiotic effect of the mold Penicillium chrysogenumPenicillinSource: Penicillin chrysogenum

Penicillin antibiotics grouped into generations based on spectrum of anti-microbial activity. (1st, 2nd , 3rd and 4th generations) Natural (penicillin G and V) Semisynthetic (Ampicillin, Carbenicillin)

ClassificationPenicillins (penicillin G) greatest activity against gram+, gram-cocci, non-beta-lactamase-producing anaerobes

Antistaphylococcal penicillins (nafcillin) resistant to staphylococcal beta-lactamases, active to staphylococci and streptococci

Extended-spectrum penicillins (ampicillin) retain antibacterial spectrum of penicillin with improved activity against gram- organisms, but are destroyed by beta-lactamases.Types of Penicillin

Chemical StructurePenicillins as well as cephalosporins are called beta-lactam antibiotics, characterized by 3 fundamental structural requirements:

the fused beta-lactam structurea free carboxyl acid groupone or more substituted amino acid side chains

- The R group is responsible for the activity of the drug and can be changed to improve activity of the antibiotic.

- Cleavage of the beta-lactam ring will render the drug inactive.Chemical structure of penicillins

StructureThiazolidine ringBeta-lactam ringVariable side chain (R group)