Transcript Micr biology o Chapter 20, part A

TORTORA • FUNKE
• CASE
Microbiology
AN INTRODUCTION
EIGHTH EDITION
B.E Pruitt & Jane J. Stein
Chapter 20, part A
Antimicrobial Drugs
Antimicrobial Drugs
•
Chemotherapy
The use of drugs to treat a disease
•
Antimicrobial drugs
Interfere with the growth of microbes within a host
•
Antibiotic
Substance produced by a microbe that, in small
amounts, inhibits another microbe
•
Synthetic
produced in a lab, not from an organism
•
Selective toxicity
A drug that kills harmful microbes without
damaging the host
Chemotherapy
• Ancient - potions, salves etc
• Graviora quaedam sunt
remedia periculus - “some
remedies are worse than
the disease” Using things
like inorganic arsenic and
mercury to treat syphilis
• Koch and germ theory
• Erlich with “magic bullet”
idea
• Fleming first Antibiotic Penicillium notatum and
penicillin with Staphylococcus
spp. 1928
• 1928 – Fleming
discovered
penicillin,
produced by
Penicillium.
• 1940 – Howard
Florey and
Ernst Chain
performed first
clinical trials of
penicillin.
Figure 20.1
Sources of some noteworthy Antibiotics
Table 20.1
Broad versus Narrow Spectrum
Table 20.2
Criteria for Ideal Antibiotics
•
Selectively toxic to microbe but nontoxic to host
•
Soluble in body- tissue distribution - blood brain barrier
•
Remains in body long enough to be effective - resists excretion and breakdown
•
Shelf life
•
Doesn’t lead to resistance
•
Cost not excessive
•
Hypoallergenic
•
Concerns suppression of normal flora - antibiotic associated colitis with Clostridium
difficile and it’s toxins or Candida albicans
•
Clostridium difficile causes approximately 20% of cases of diarrhea associated with
antibiotics, including clindamycin and the second- and third-generation
cephalosporins. Diarrhea is usually mild, but can be severe; extreme cases develop
toxic megacolon
C. diff
•
Figure 1. Features of C difficile colitis:
•
A) Plain film of abdomen showing bowel wall
thickening, loss of haustral markings (thin arrow)
and dilation of the ascending and transverse colon
(thick arrow);
•
B) Computed tomographic scan of abdomen
showing colonic dilation (thin arrows) and bowel
wall thickening with stranding (thick arrow);
•
C) Endoscopic view of classic C difficile
associated pseudomembranous colitis (arrows
mark pseudomembranes).
http://www.cfpc.ca/cfp/2004/Nov/vol50-nov-cme-1.asp
Mechanisms of Action
Targets of antibacterial agents - many ways to attack
• Cell Wall - peptidoglycan - Gram (+) vs (-) and forms “weak points”
and are osmotically fragile easily lysed
•  lactams like Penicillins and cephalosporin react with enzymes in
formation of cross links
• Cycloserine inhibits subunits of peptidoglycan
• Vancomycin hinders the elongation of peptidoglycan
• Bacitracin interferes with transport of precursors across plasma
membrane
• Nucleic acid synthesis
• Inhibition of transcription and DNA replication
• Sulfonamides - sulfa drugs block PABA to folic acid used to make
nucleotides by competitive inhibition of enzyme trimethoprim and
sulfamethoxazole SXT
• Often toxic - allergic reactions
Mechanisms of Action - continued
• Protein synthesis - different ribosomes 70s good site of attack
• Aminoglycosides - (streptomycin, gentamicin) bind to 30s subunit
blocks translation and misreading of mRNA
• Tetracyclines - bind to 30s subunit and block attachment of tRNA
• Chloramphenicol - binds to 50S subunits and prevents peptide
bonds from being formed
• Macrolides - bind to 50s subunits and prevents the continuation of
protein synthesis - used in many G(+) and walking atypical
pneumonia instead of penicillin
• Plasma membrane attack
• Polymyxin - binds with phospholipids in membrane - not as
selectively toxic - topical
• Inhibition of enzymatic activities
• Like sulfa and PABA blocked to folic acid
The Action of Antimicrobial Drugs 
Figure 20.2
The Action of Antimicrobial Drugs
Figure 20.4
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Penicillin
• Natural penicillins
• Natural from mold
• Choice for
Streptococcus spp
and most
Staphylococcus
spp
• Semisynthetic penicillins
• More resistant to
penicillinase
• Methicillin-resistant
Staphylococcus
aureus (MRSA)
Penicillins
Figure 20.6
Penicillinase
Figure 20.8
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Semi-Synthetic Penicillin
• Penicilinase-resistant
penicillins
• Extended-spectrum
penicillins
• Penicillins + lactamase inhibitors
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
Cephalosporins
• Different mold
source
• more effective
against gramnegatives
• More resistant
penicillases
Figure 20.9
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Polypeptide antibiotics
• Bacitracin - Margaret Tracey - 1945, 7 years old, hit by
car, compound fracture contained B. subtilis that killed
S. aureus
Anne Margaret
• Topical application
Tracey
• Against gram-positives
• Vancomycin
born 15 February 1936
• Glycopeptide
• Important "last line" against antibiotic resistant S.
aureus
• vancomycin-resistant enterococci (VRE)
• Enterococcus faecium and Enterococcus faecalis
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Antimycobacterium antibiotics
• Isoniazid (INH)
• Inhibits mycolic acid synthesis
• Ethambutol
• Inhibits incorporation of mycolic acid
Multidrug-Resistant Tuberculosis
Infection
Antibacterial Antibiotics
Inhibitors of Protein Synthesis
• Chloramphenicol
• Broad spectrum
• Binds 50S subunit, inhibits peptide bond
formation
• Aminoglycosides
• Streptomycin, neomycin, gentamycin
• Broad spectrum
• Changes shape of 30S subunit
Antibacterial Antibiotics
Inhibitors of Protein Synthesis
• Tetracyclines
• Broad spectrum
• Interferes with tRNA attachment
• Macrolides
• Gram-positives
• Binds 50S, prevents translocation
• Common macrolides
• ▪Azithromycin (Zithromax)
• ▪Clarithromycin (Biaxin, Fromilid)
• ▪Dirithromycin (Dynabac)
• ▪Erythromycin
• Gram-positives
• Binds 50S, prevents translocation
Antibacterial Antibiotics
Inhibitors of Protein Synthesis
• Streptogramins
• Gram-positives
• Binds 50S subunit, inhibits translation
• Synercid
• Gram-positives
• Binds 50S subunit, inhibits translation
• Oxazolidinones
• Linezolid
• Gram-positives
• Binds 50S subunit, prevents formation of 70S
ribosome
Antibacterial Antibiotics
Injury to the Plasma Membrane
• Polymyxin B
• Topical
• Combined with bacitracin and neomycin in overthe-counter preparation
Antibacterial Antibiotics
Inhibitors of Nucleic Acid Synthesis
• Rifamycin
• Inhibits RNA synthesis
• Antituberculosis
• Quinolones and fluoroquinolones
• Ciprofloxacin
• Inhibits DNA gyrase
• Urinary tract infections
Antibacterial Antibiotics
Competitive and Noncompetitive Inhibitors
• Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Figure 5.7
Sulfa drugs as inhibitors
Figure 20.13