Transcript Control of microbial growth: Sterilization and disinfectants

Antimicrobial Therapy
• Chemotherapy: any treatment of patient with chemicals to
treat a condition.
– Now word associated with cancer treatment
– Our focus is on antimicrobial agents
• Antimicrobials: synthetic, antibiotics, or semi-synthetic
– Antibiotics: natural products made by microbes, effective against
other microbes
– Semi-synthetic antibiotics: use natural antibiotic as base, but
modified chemically; most of our new “antibiotics”
– Antibiotics are “small molecules”, 500 MW, not to be at all
confused with antibodies which are proteins (MW 150,000)
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Spectrum
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• Some antibiotics are considered “broad spectrum”
– By definition, these are effective against many types of
bacteria
– Since the most resistant bacteria are often Gram negative,
because of their OM, we often think of broad spectrum
antibiotics being those that also work against many G– Broad spectrum antibiotics can sometimes cause
problems because of damage to normal microbiota of
host
– “Superinfection” may result from this situation
Selective Toxicity:
the key to antibiotic therapy
• Basic pharmacology: any
biologically active substance
will have a level at which there
is no effect, a level where it will
do what you want (kill
microbes), and a level that will
be toxic.
Selective toxicity is the ability of the drug to harm the target
without harming the host. Bacteria have many targets that are
biologically different from us that the drugs can hit. As the
target becomes more like us, there are fewer and fewer drugs
that are selectively toxic: fungi, protozoa, worms, viruses,
cancer.
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Selective Toxicity and side effects
•Drugs may fail to be selectively toxic and interfere with
mammalian biochemistry. They may cause allergies. They
may destroy too many normal bacteria.
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Actions of antimicrobials
• Drugs work against microbes by these basic mechanisms:
– Inhibition of cell wall synthesis
• Causes bacterium to commit suicide, but only during
growth when cells are cutting their own PG.
– Disruption of membrane function
• Often toxic to humans because we have membranes
too, cause leakage of vital molecules.
– Inhibition of protein synthesis – many antibiotics
• Bind to ribosomal RNAs, proteins.
– Inhibition of nucleic acid synthesis
• Attack transcription, DNA unwinding enzymes
– Act as anti-metabolites – competitive inhibitors, inhibit
function of enzymes, usually bacteriostatic.
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Ideal Antibiotic
• Good drug properties (e.g. soluble in body fluids)
• Selectively toxic, obviously
• Constant toxicity, not influenced by host condition
or behavior
• Non-allergenic
• Stable in vivo, slowly broken down and excreted
• Difficult to become resistant to
• Long shelf life
• low $
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HOW resistance is Acquired
• Non-genetic: Evasion, bacteria may hide in cells or
organelles; L-forms, temporary forms of cell w/o
cell walls, removing a target.
• Mutations: change in transport protein, ribosome,
enzyme, etc. Normally harmful mutations are
selected FOR in the presence of antibiotic.
• Plasmids: through conjugation, genetic information
allowing cell to overcome drug.
http://www.mun.ca/biochem/courses/3107/
images/Stryer/Stryer_F32-13.jpg
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Mechanisms of drug resistance
• Alteration of target: active site of enzyme changes,
ribosome changes.
• Alteration of membrane permeability: transport
protein changes, drug no longer enters; drug that
does enter is actively pumped out.
• Enzymatic destruction of drug: penicillinases (beta
lactamases)
• “End around” inhibitor: bacteria learns to use new
metabolic pathway, drug no longer effective.
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Human behavior and antibiotic resistance
• Bacteria once under control are making a comeback due to
antibiotic resistance:
– S. aureus, Enterococcus, M. tuberculosis, et al.
• Human behavior:
– Most diseases caused by viruses, non-cellular, not
treatable with antibiotics (but Doctor, do something)
– Full time course needed; last bacteria left are the most
resistant, if they aren’t killed, they become “normal”;
don’t stop regimen because you feel better.
• Social behavior
– resistance in homeless/poor
– growth stimulants in agriculture
http://www.dkp-ml.dk/images/homeless.jpg
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Fighting antibiotic resistance
• Use all drug at sufficiently high concentration
– Don’t allow the least sensitive bacteria to survive
• Drugs in combination
– Odds of mutating to resist 2 drugs: 1 in 106 x 106
– Synergism: e.g. amoxicillin and clavulanic acid
• Limit antibiotic use
– >50% of infections are viral; not affected by antibiotics
– Constant exposure breeds resistance
• New drugs
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MRSA: how it does it
• Methicillin-resistant Staph. aureus
– Acquired in hospitals and the community
– Now only treatable with vancomycin
• Only injected
• More likely to cause side effects
• Beta lactam antibiotics bind to transpeptidases
– “PBPs”, build peptidoglycan;
– Mutant protein PBP 2a has altered structure including
altered active site; methicillin cannot bind
– One good transpeptidase keeps bacterium alive
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