Title: Drugs, Microbes, Host The Elements of Chemotherapy
1Drugs, Microbes, Host The Elements of
Chemotherapy
Chapter 12
2How you should approach this chapter
- Antimicrobial chemotherapy and antimicrobics
- What are selection criteria?
- How are they used?
- What are adverse effects?
- HOW DO THEY WORK (what is their mode of action)?
- Blocks or inhibits
- Cell wall synthesis
- nucleic acid structure/function
- protein synthesis
- cell membrane structure/function
- (Specific metabolic pathways)
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- Antibacterial drugs Antibiotics and Synthetics
(what is the difference?) - Classes/categories know source, mode of action,
application/spectrum - Antibiotics penicillins, cephalosporins, other
B-lactam Abt, aminoglycosides, tetracyclines and
other Streptomyces antibiotics, Bacillus
antibiotics, other new drugs - Synthetics sulfonamides, flouroquinolones,
others (narrow and broad spectrum)
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- Other antimicrobials antifungals, antiprotozoal,
anthelminthics, antiviral. - Drug resistance How? Why? Effect?
- Side effects of drugs toxicity, allergy,
superinfection - Skim pp. 375-379
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7Origins of antimicrobial drugs
- Antibiotics are common metabolic products of
aerobic spore-forming bacteria fungi. - bacteria in genera Streptomyces Bacillus
- molds in genera Penicillium Cephalosporium
- By inhibiting the other microbes in the same
habitat, antibiotic producers have less
competition for nutrients space.
8Selectively toxic
- Drugs should kill or inhibit microbial cells
without simultaneously damaging host tissues. - As the characteristics of the infectious agent
become more similar to the vertebrate host cell,
complete selective toxicity becomes more
difficult to achieve more side effects are seen.
9Targets of antimicrobial drugs
- Inhibition of ____________________
- Inhibition of ____________________
____________________ - Inhibition of ____________________
- Disruption of ____________________
____________________
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111. Drugs that affect the bacterial cell wall
- Penicillin and cephalosporin block synthesis of
peptidoglycan, causing the cell wall to lyse. - Other drugs include vancomycin, bacitracin,
monobactams, fosfomycin, cycloserine
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132. Drugs that inhibit nucleic acid synthesis
- may block synthesis of nucleotides, inhibit
replication, or stop transcription - ____________________ drug competes with normal
substrate for enzymes active site - ____________________ an additive effect,
achieved by multiple drugs working together,
requiring a lower dose of each
142. Drugs that inhibit nucleic acid synthesis
- Sulfonamides and trimethoprim (synergistic) --
block enzymes required for tetrahydrofolate
(THFA) synthesis - THFA is needed for DNA RNA synthesis.
(coenzyme) - Quinolones (ciprofloxacin) blocks gyrase
- Rifampin blocks RNA pol (transcription)
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163. Drugs that block protein synthesis
- Ribosomes of eucaryotes differ in size and
structure from procaryotes, so antimicrobics
usually have a selective action against
procaryotes. But they can also damage the
eucaryotic mitochondria. - Abt can block mRNA, peptide bonds, tRNA binding,
etc.
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184.Drugs that disrupt cell membrane function
- A cell with a damaged membrane dies from
disruption in metabolism or lysis. - These drugs have specificity for a particular
microbial group, based on differences in types of
lipids in their cell membranes. - Polymyxins interact with phospholipids and cause
leakage, particularly in gram-negative bacteria - Amphotericin B and nystatin form complexes with
sterols on fungal membranes which causes leakage.
194. Drugs that disrupt cell membrane function
20Survey of major antimicrobial drug groups
- Antibacterial drugs
- Antibiotics
- Synthetic drugs
- Antifungal drugs
- Antiparasitic drugs
- Antiviral drugs
- About 260 different antimicrobial drugs are
classified in 20 drug families.
21Antibacterial antibiotics
- Penicillins
- Cephalosporins
- Other beta-lactam antibiotics
- Aminoglycosides
- Tetracycline antibiotics
- Chloramphenicol
- Other Streptomyces antibiotics
- The Bacillus antibiotics
- New classes
22Penicillins
- Source Penicillium
- Examples -cillin such as penicillin,
ampicillin, amoxicillin, methicillin etc. - MOA blocks PGN synthesis (CW)
- Application Gram positive, some Gram neg.
- Structure B-lactam, thiaxolidine, varying side
chains - Problems allergy, bleeding, diarrhea(host)
resistance in bacteria (via lactamase,
penicillinase)
23Penicillins
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25Cephalosporins
- Source Cephalosporium
- Examples Ceph- cef- kef- drugs (ex. Cephalexin)
- MOA blocks CW synthesis
- Application depends on generation
- Structure B-lactam, ring, varying side chains
(2) - Problems less allergies, but some need
parenteral administration, can affect WBC
26Cephalosporins - generations
27Other beta-lactam antibiotics
- Imipenem broad-spectrum drug for infections
with aerobic and anaerobic pathogens - Aztreonam isolated from bacteria Chromobacterium
violaceum newer narrow-spectrum drug for
infections by gram-negative aerobic bacilli. May
be used by people allergic to penicillin- it is a
monobactam.
28MOA of B-lactam antibiotics
- PGN (made of NAM and NAG) are cross-linked by the
enzyme transpeptidase - This is the final step in CW syntheis
- B-lactam abt inhibit transpeptidase they mimic
the normal substrate and bind to the active site.
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30aminoglycosides
- Source Actinomycetes (like Streptomyces)
- Examples streptomycin, gentamicin, amikacin,
neomycin - MOA blocks translation (inhibits initation,
binds 30S ribosomal subunit) - Application relatively broad
- Structure 6C ring with 2 amino sugars
- Problems diarrhea, kidney, EAR problems
31Aminoglycosides
32Other antibiotics produced by StreptomycesA.
Tetracyclines
33tetracyclines
- MOA block protein synthesis (30S)
- Application Broad-spectrum, Doxycycline
minocycline oral drugs taken for STDs, Rocky
Mountain spotted fever, Lyme disease, typhus,
acne protozoa - Problems kills GI flora, can discolor teeth in
children, causes photosensitization
34B. Chloramphenicol
- Source Streptomyces venezuelae is totally
synthetic now - MOA Blocks peptide bond formation
- Application Potent broad-spectrum drug with
unique. Typhoid fever, brain abscesses,
rickettsial chlamydial infections - Structure nitrobenzene
- Problems Very toxic, restricted uses, can
cause irreversible damage to bone marrow
35C. Erythromycin
- MOA Attaches to ribosome (50S)
- Application
- Broad-spectrum, fairly low toxicity.
- Taken orally for Mycoplasma pneumonia,
legionellosis, Chlamydia, pertussis, diptheria
and as a prophylactic prior to intestinal surgery - For penicillin-resistant gonococci, syphilis,
acne - Newer semi-synthetic macrolides clarithomycin,
azithromycin - Structure macrolide, large lactone ring with
sugars
36Macrolide antibiotic
37Other Streptomyces antibiotics
- Clindamycin broad-spectrum, serious abdominal
anaerobic infections - Vancomycin narrow-spectrum, effective against
penicillin methicillin resistant staphylococcal
infections very toxic, hard to administer
inhibits CW synthesis (NAM/NAG polymerization) - Rifampin limited spectrum, cannot pass through
many cell membranes, used to treat gram-positive
bacteria, TB, leprosy - Blocks TRANSCRIPTION
38The Bacillus antibiotics
- Bacitracin-
- MOA Blocks CW synthesis
- Application narrow-spectrum, major ingredient of
neosporin ointment - Polymyxin
- MOA peptide with fatty acid component, detergent
activity - Application narrow-spectrum drug resistant
Pseudomonas aeruginosa UTI - Problems limited by toxicity to kidney
39New classes of antibiotics
- Fosfomycin trimethamine a phosporic acid
effective as alternate treatment for UTIs,
inhibits cell wall synthesis - Synercid effective against Staphylococcus
Enterococcus that cause endocarditis surgical
infections inhibits protein synthesis (binds
50S)
40II. Synthetic antibacterial drugs
- Sulfonamides, sulfa drugs first antimicrobic
drugs - Sulfisoxazole shigellosis, UTI, protozoan
infections - Silver sulfadiazine burns, eye infections
- Trimethoprim given in combination with
sulfamethoxazole UTI, PCP - Sulfonamides and trimethoprim block THFA synthesis
41A. Sulfonamides
42B. Miscellaneous antibacterial drugs
- Isoniazid used with rifampin to treat TB blocks
FA reductase (metabolism) - Oxazolidinones- new class of antibacterial drugs
inhibit initiation of protein synthesis - Linezolid MRSA, VRE
- Fluoroquinolones broad-spectrum, potent block
prokaryotic gyrase - norfloxacin, ciprofloxacin UTI, STD, GI,
osteomyletitis, respiratory soft tissue
infections - sparofloxacin, levofloxacin pneumonia,
bronchitis, sinusitis