Exam 3: Topic 14 Flashcards
List four targets of antibacterial drugs.
• Cell wall synthesis
• Protein synthesis
• RNA Synthesis
• DNA replication
• Metabolic pathways
• Cell membrane integrity
Explain why selective toxicity is an important parameter to consider when researching or prescribing antimicrobial drugs
• toxic to bacteria @ low dose. requires a high dose to be toxic to humans
Differentiate between broad spectrum and narrow spectrum drugs. Provide one clinical example of where a broad-spectrum agent is preferred and one where a narrow spectrum agent is preferred.
• Broad spectrum is preferred in emergency setting or unknown situation; Narrow preferred when specific target is known and to not disrupt normal flora, such as normal flora in colon that can lead to a different/worse infection.
• Narrow spectrum: kills small subset of infectious bacteria
• Broad spectrum: kills most infectious bacteria
BIG OBJECTIVE: Describe, in detail, the two major drug classes that target peptidoglycan synthesis.
a) What is their mechanism of action?
b) Diagram the chemical structure of these drugs, and identify the nucleus, the Beta-lactam ring, and the varying side chain.
c) How does varying the side chain alter the properties of the drug?
A. Mechanism of Action for Penicillins and Cephalosporins:
Block transpeptidase, enzyme is not able to establish crosslink and weakens peptidoglycan structure, which then cannot counteract water influx into cell and the cell lyses.
C. Strategic chemical changes to the R groups have allowed for development of a wide variety of semisynthetic β-lactam drugs with increased potency, expanded spectrum of activity, and longer half-lives for better dosing.
BIG OBJECTIVE! Explain the history of the penicillin drugs as described in class, including some of the motivations for developing additional generations.
• Although the β-lactam ring must remain unchanged for these drugs to retain theirantibacterial activity, strategic chemical changes to the R groups have allowed for development of a wide variety ofsemisynthetic β-lactam drugs with increased potency, expanded spectrum of activity, and longer half-lives forbetter dosing, among other characteristics.
• Adding an amino group (-NH2) to penicillin G created the aminopenicillins that have increased spectrum of activity against more gramnegative pathogens. Furthermore, the addition of a hydroxyl group (-OH) to amoxicillin increased acid stability,which allows for improved oral absorption.
• Methicillin is a semisynthetic penicillin that was developed to addressthe spread of enzymes (penicillinases) that were inactivating the other penicillins. Changing the R group of penicillinG to the more bulky dimethoxyphenyl group provided protection of the β-lactam ring from enzymatic destruction by penicillinases, giving us the first penicillinase-resistant penicillin.
• cephalosporins also contain a β-lactam ring and block the transpeptidaseactivity of penicillin-binding proteins. However, the β-lactam ring of cephalosporins is fused to a six-member ring,rather than the five-member ring found in penicillins. This chemical difference provides cephalosporins with anincreased resistance to enzymatic inactivation by β-lactamases.
• Similar spectrum of activity to that of penicillinagainst gram-positive bacteria but is active against more gram-negative bacteria than penicillin. Another importantstructural difference is that cephalosporin C possesses two R groups, compared with just one R group for penicillin,and this provides for greater diversity in chemical alterations and development of semisynthetic cephalosporins.The family of semisynthetic cephalosporins is much larger than the penicillins, and these drugs have been classifiedinto generations based primarily on their spectrum of activity, increasing in spectrum from the narrow-spectrum,first-generation cephalosporins to the broad-spectrum, fourth-generation cephalosporins. A new fifth-generationcephalosporin has been developed that is active against methicillin-resistant Staphylococcus aureus (MRSA).
Some bacteria are resistant to penicillin drugs (and to a lesser extent, cephalosporins). What enzyme do these resistant bacteria possess?
• Ɓ-lactamase.
This enzyme works cutting the b-lactam ring. B-lactamases are not as effective against the B-lactam ring of cephalosporins.
What is Augmentin? Why might physicians prescribe Augmentin over amoxicillin?
• Amoxicillin has a moderate spectrum of activity (most G+, some G-)
• Augmentin is combo drug. It is basically amoxicillin with a B-lactamase inhibitor. Used as a secondary prescription incase the first does not work or if the infection shows resistance to amoxicillin.
Explain why methicillin is often effective against Staphylococcus pathogens resistant to other forms of penicillin.
• Bulky side chain protects B-lactam ring from B-lactamase
Explain why cephalosporins tend to be more resistant to Beta-lactamase than penicillins.
• The carboxylic acid group (from carbon #2) blocks the b-lactamase from cutting the b-lactam ring. B-lactamases are not as effective against the B-lactam ring of cephalosporins
Explain how MRSA developed resistance to methicillin
• Resistant to every penicillin drug, including methicillin.
• Preventing the drug to getting to the active site
• or cutting the b-lactam ring
• develop resistance to methicillin (MRSA) throughthe acquisition of a new low-affinity Penicillin binding proteins, rather than structurally alter their existing PBPs.
• Genetic changes impacting the active site of penicillin-binding proteins(PBPs) can inhibit the binding of β-lactam drugs and provide resistance.
Describe the mechanism of action of vancomycin.
• Only works against G+ bacteria; too big to get through the porins of G-.
• Complexes with tetrapeptides in peptidoglycan. Obstructionist activity physically blocks transpeptidase from adding crosslink. Weakens peptidoglycan and cell lyses.
Why aren’t Beta-lactamases effective against vancomycin? Why is this important in combating MRSA?
• B-lactamases are not effective against vancomycin, because there is not b-lactam ring present.
• This is important in combating MRSA, because MRSA is able to cut the b-lactam ring or blocks other drugs from getting to their active site and can still synthesize peptidoglycan. Vancomycin is effective, because the obstructionist activity physically blocks transpeptidase from adding crosslink.
Explain how an antibiotic might target bacterial DNA synthesis without hindering DNA synthesis in our own cells. Which class of antibiotics works this way? What enzymes do these drugs inhibit?
Fluoroquinolones: target and inhibit DNA gyrase. It is a bacterial enzyme and not present in humans.
Name and describe the basic mechanism of action for the five antibiotics that target protein synthesis (as discussed in class). Which four affect the bacterial ribosomes? Which one affects RNA polymerase?
I. Pencillins and cephalosporins: actively inhibit transpeptidase.
II. Augmentin: B-lactamase inhibitor.
III. Methicillin: bulky side chain protects B-lactam ring from B-lactamase
IV. Vancomycin: Complexes with tetrapeptides in peptidoglycan = obstructionist activity physically blocks transpeptidase from adding crosslink
Why are some ribosome inhibitors still toxic to humans?
• Because they target the ribosomes in our mitochondria.
• Target machinery in mitochondrial ribosome and cannot generate ATP.
• Mitochondrial function is often impaired (e.g. mitochondrial ribosomes are same size as bacterial ribosomes)
○ Less ATP
○ Organ toxicity (especially kidney and liver)
