Antibacterial Inhibitors of Cell Wall Synthesis

– Very high therapeutic index• Low toxicity with high effectiveness

• β- lactam Drugs– Inhibit peptidoglycan synthesis – Only effective against growing bacteria– Vary in their spectrum of activity

Penicillinase cleaves the β–lactam ring from the common nucleus of penicillin compounds

•Some bacteria produce β- lactamase enzymes •Destroys β- lactam ring which inactivates drug

•Greater variety produced by G- bacteria

• Penicillins– group of over 50 related antibiotics– share a common core structure – Natural penicillins

• have a narrow range of activity – Semisynthetic penicillins

• overcome disadvantages

• Natural Penicillin– Produced by the mold Penicillium chrysogenum– Most common are Penicillin G and Penicillin V– Narrow spectrum

• Effective against Gram + and few Gram – cocci

• Semi-synthetic Penicillin– Penicilinase-resistant penicillins

• Methicillin – MRSA reduced use

– Penicillins + -lactamase inhibitors• Augmentin

– Combines amoxicillin with clavulanic acid which inhibits penicillinase

•Cephalosporins•Produced by mold Acremonium cephalosporium

•resemble penicillin

•broader spectrum

•Semi-synthetic versions grouped as generations

•New generations less susceptible to β -lactamases

• Polypeptide antibiotics

– Bacitracin• Produced by species of Bacillus • Topical application due to toxicity• effective primarily against G+ bacteria

– Vancomycin• Produced by species of Streptomyces • Has narrow spectrum similar to penicillin • Used to treat antibiotic-associated colitis • Important "last line" against MRSA and VRE

• Antimycobacterial drugs – effective only against Mycobacterium

– Isoniazid • Inhibits mycolic acid synthesis

– Ethambutol • Inhibits incorporation of mycolic acid

• Bind 30S subunit

• Aminoglycosides– Produced by Streptomyces spp.– Broad spectrum– Streptomycin, neomycin, gentamycin, tobramycin

• serious side effects • Streptomycin is an alternative treatment for

tuberculosis– resistant strains rapidly emerging

Antibacterial Inhibitors of Protein Synthesis

• Tetracyclines

– Produced by Streptomyces – Oxytetracycline, Doxycycline – Broadest spectrum of all anti-bacterial drugs

• Effective against most G- and G+ bacteria; rickettsias and chlamydias

– Common animal feed additive

• Bind 50S subunit

• Chloramphenicol– Produced by Streptomyces– Very simple chemical structure and inexpensive– Broad spectrum– Serious toxicity issues

• Macrolides– Erythromycin , azithromycin

– Choice mycoplasmal pneumonia

• Oxazolidinones– Narrow spectrum (mostly G+), totally synthetic

• resistance develops slower• Useful against vancomycin and β- lactam resistant

bacteria

Antibacterial Injury to the Plasma Membrane

• Polymyxin B– Useful against G- bacteria & G+– One of the 1st antibiotics useful against G-

Pseudomonas– Topical

• Combined with bacitracin and neomycin in over-the-counter preparation (neosporin)

Antibacterial Inhibitors of Nucleic Acid Synthesis

• Rifamycin– Rifampin – Inhibits RNA synthesis in prokaryotes – Effective against Gram+, Gram- and mycobacterium – Used in treatment of tuberculosis and prophylactic

prevention of meningitis • Penetrate tissues so capable of reaching cerebrospinal fluid and

abscesses

• Fluoroquinolones– Synthetic Drugs – Broad spectrum – Ciprofloxacin– Inhibits enzyme needed for DNA replication– Adversely effect the development of cartilage

• limited use in children and pregnant women

Antibacterial Anti-metabolites Sulfonamides (Sulfa

drugs)• Broad spectrum• Inhibit folic acid synthesis

Trimethoprim • Used in combination with sulfa drugs

– broader spectrum and reduces the risk of resistance