Antimicrobial Drugs Extra Resource for Lab

 

In lab, you were introduced to the concept of microbial control:  the strategies we use to keep pathogenic microbes from keeping us sick, or to eliminate those that are making us sick.  We discussed the fact that there are really two different facets to this conversation:  controlling microbes in the environment around us, and controlling the microbes that have made it into our bodies already.  

 

There are two general strategies for controlling pathogenic microbes in the environment (shown in green above)

• Physical Control Methods (i.e. temperature, UV light, radiation, filtration)
• Chemical Control Methods (i.e.  detergents and soaps, chemicals that alter the pH, alcohol, aldehydes) 

 

Analyzing physical and chemical methods to control microbial growth: There are lots of ways to control
microbes in the environment, but they all fall into four basic categories.

A. Decrease Cell Integrity: alterations in the cell walls or cell membranes to disrupt the integrity of the cell
B. Disrupt proteins: interfering with protein structures to disrupt metabolism and the way the cell functions.
C. Disrupt nucleic acids: interfering with nucleic acid structures interferes with protein production and reproduction
D. Degerming: removal of microbes from the surface or area

 

While these strategies are really useful in the environment, we cannot use disinfectants or harsh physical methods to eliminate pathogens inside the body as they are toxic to humans and may damage our tissues along with the infectious microbe. Instead, we use antimicrobial drugs (in red on the diagram above) to control different microbes including bacteria, fungi, parasites (protozoa and worms) and viruses.

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Antimicrobial Drugs

Most antimicrobial drugs work to control the growth of microbes by using one of the following strategies:

• Decrease cell integrity:  Agents that target the cell wall or plasma membrane
• Disrupt protein production:  Agents that affect the ability of the microbe to make proteins
• Disrupt genome production/expression:  Agents that target genome replication and transcription
• Disrupt attachment:  Agents that disrupt attachment of microbes from their target receptors
• Disrupt metabolism: Agents that disrupt energy production or the production of building blocks (i.e. amino acid production, nucleic acid production)
• Disrupt structure:  Agents that disrupt large scale structures (i.e. scolex, muscles in helminths)
• 
  

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Drug Design and Selection

When designing drugs or choosing the proper drug to prescribe, there are lots of considerations including:

1. Selective Toxicity:  the drug should be toxic to the microbe without being toxic to the host.  This is not to say that drugs that are toxic to the host are never used, it is just that they are used MUCH less often.  The risk of the infection would have to be greater than the risk of the toxic effects of the drug.  

 

2. Target of Treatment: the drug must act on a target that actually exists in the microbe.  For example, a drug that targets the bacterial ribosome is an excellent choice for treating a bacterial infection.  However, a drug that targets the bacterial ribosome is a poor choice for treating a virus (doesn't have a ribosome at all) or a fungi, protozoa or helminth infection (all contain eukaryotic ribosomes rather than bacterial ribosomes).

 

3. -cidal treatments vs. -static treatments:  A drug that kills the targeted microbe are considered -cidal drugs.  However, not all drugs kill the microbe they are targeting.  Some drugs inhibit the growth and reproduction of the targeted microbe.  These drugs are considered -static drugs.  Static drugs are used to restrict the growth and spread of the microbe.  

 

4. Spectrum of antimicrobial activity: the drugs that we use affect different populations of microbes.  There are drugs that affect bacteria, drugs that affect fungi, drugs that affect helminths, etc.  Even within these groups, there are drugs that affect only subsets of the group.  (see the figure below).  A drug that targets all or most of the microbes in a group (for example, tetracycline), is considered a broad spectrum antimicrobial.  One that is very specific for only a small subset of the microbes in a group are considered narrow spectrum antimicrobials (for example, penicillin).  The range of activity is determined by the target of the drug.  Tetracycline affects the ribosome, which all bacteria have and so it is broad spectrum.  Penicillin targets the peptidoglycan, which is only accessible in gram positive bacteria and is therefore a narrow spectrum drug.  Spectrum is determined within target microbe group. Even a broad spectrum antibiotic doesn’t target viruses or any of the eukaryotic pathogens. 

 

 

5. Drug Resistance:  We've talked about ways that antimicrobial resistance can emerge in a population of microbes (spontaneous or induced point mutations and horizontal gene transfer) and how exposure to antimicrobial drugs kills susceptible microbes and leaves behind a population of microbes that is resistant to the drugs. We've talked about how some viruses, especially, accumulate those mutations VERY quickly (think about HIV and SARS CoV-2) Today, we are going to think about impacts and complications that arise when microbes having or are able to attain that kind of drug resistance when we are thinking about how to help patients by prescribing them antimicrobial drugs.  

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A note on drugs & spectrum!!

Sometimes the theory of a drug is a bit different from the effect we observe in the lab. This can tell us important information about the chemical properties of specific drugs. Depending on the chemical properties of a drug, this can influence how the drug gets into organisms.

Take a note on aminoglycosides in the figure below. The uptake is mediated through pores present in the OM as illustrated. Although the target (bacterial ribosomes) would suggest a broad-spectrum effect, what class of bacteria would most likely be affected the most?

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