Chapter 25 — Exercises
Antimicrobial Peptides: The Natural Weapons That Could Solve Antibiotic Resistance
Work these with the chapter open. Items marked † are extended problems suitable for seminar discussion, written assignment, or assessment; they generally require more than one section and usually have no single correct answer.
No answers are given here. Answers to the quiz are in quiz.md; instructors have a full answer set.
A reminder before you start. Nothing in this chapter or these exercises is guidance about treating an infection. Untreated bacterial infection is a medical emergency, and every clinical decision in this area belongs with a clinician who can examine a patient and order a culture.
Part 1 — Getting the facts straight
A. State the number of deaths directly attributable to bacterial antimicrobial resistance for the year given in §25.1. Give the year. Then state the associated figure and explain, in two sentences, what makes them different quantities.
B. A press release says "antibiotic resistance kills nearly five million people every year." Is this false? Explain your answer in a way that does not use the word "wrong."
C. List the three structural features that recur across antimicrobial peptides (§25.2). For each, say what job it does in the killing mechanism.
D. Name the two classes of human defensin and say where each is found. Then name the only human cathelicidin.
E. From what organism were magainins isolated, in what year were they described, and what observation prompted the search?
F. Define, in one sentence each: minimum inhibitory concentration, hemolysis, selectivity index.
G. Name four peptide antibiotics that are currently approved and in clinical or commercial use. For each, state whether it is used topically, systemically, or neither.
H. What is mcr, what does the enzyme it encodes do to the bacterial surface, and why does the word "plasmid" matter so much in that sentence?
I. In what year was daptomycin first approved, and for what class of indication? Name the one common infection for which it is not used, and give the biochemical reason.
Part 2 — Mechanism and reasoning
J. Explain in your own words why a single point mutation can confer resistance to a target-specific antibiotic but is unlikely to confer resistance to a membrane-disrupting peptide. Then state the strongest objection to that argument.
K. The three models of membrane disruption in §25.3 make different physical predictions. For each model, describe one experimental observation that would be more consistent with it than with the other two.
L. † The chapter says AMPs work by "the exact opposite logic" to the receptor-mediated peptides of Chapter 2. Write 400–600 words setting out the contrast systematically: targeting, concentration required, amplification, specificity, and reversibility. Conclude by stating which of these differences is most responsible for the selectivity problem, and defend the choice.
M. A peptide is described as "highly cationic and strongly amphipathic." Predict two things about its behavior and one thing about its likely liability, using only §25.2 and §25.5.
N. Bacterial membranes are described as "more negatively charged." More negatively charged than what, exactly, and on which leaflet? Explain why the leaflet matters.
O. Explain why cholesterol content is relevant to AMP selectivity, and predict what would happen to a given peptide's selectivity index if it were tested against a mammalian cell line with artificially depleted membrane cholesterol.
P. † A researcher reports a novel peptide with an MIC against E. coli lower than any previously published AMP. Write the three questions you would ask before treating this as an important result, and explain what a disappointing answer to each would imply.
Q. Neutrophils release defensins into the phagosome rather than into the surrounding tissue. Explain what problem this solves, and name two other strategies the body uses to achieve the same end.
R. Explain how each of the following contributes to the gap between in vitro potency and in vivo effect: serum protein binding, physiological salt concentration, host and bacterial proteases.
Part 3 — Evidence ratings
S. Rewrite each of the following as a properly formed claim that could carry a rating — with a population and an endpoint — then assign a rating and give a one-sentence reason.
- "LL-37 is antimicrobial."
- "Colistin is dangerous."
- "Antimicrobial peptides are the future of antibiotics."
- "Teixobactin is resistance-proof."
T. The chapter rates colistin ✅ while describing nephrotoxicity and neurotoxicity in the same paragraph. Explain why this is not a contradiction, and state in one sentence what ✅ asserts and what it does not.
U. The chapter rates "AMPs cannot generate resistance" as ❌ and "AMPs will provide new systemic antibiotics" as 🔬. Both concern the same molecules. Using Chapter 5's rules, explain why both ratings are correct simultaneously.
V. † Write a complete four-line 📊 Evidence Rating block for the claim: "Inhaled murepavadin
will treat drug-resistant Pseudomonas lung infection." Use only what the chapter tells you.
Your "what would change it" line must be bidirectional and must specify at least one safety endpoint.
W. Consider the claim: "A cream containing an engineered antimicrobial peptide speeds healing of infected wounds." What single feature of the pexiganan trials described in §25.7 makes this claim harder to establish than it first appears?
X. † The chapter says a 🔬 that does not name a resolving observation "is not a rating, it is a shrug." Find two examples of "more research is needed" in any source you like — a news article, a review paper, a product page — and rewrite each as a specific, dated, bidirectional resolving observation. Then say which of the two was harder, and why.
Y. For each rating symbol, write one sentence describing a situation in which a careless writer would use it when a different symbol was correct.
Part 4 — Economics and structure
Z. Draw or describe the two revenue curves in §25.6 without looking at the figure. Then state, in one sentence, why the second curve is evidence that the clinical system is working properly.
AA. Explain why a high cost of goods is tolerable for a chronic therapy and intolerable for an antibiotic. Your answer should not use the word "expensive."
AB. † Four remedies for the antibiotic market are described in §25.6. Choose the one you find most persuasive and write 400–600 words defending it, including at least two concrete objections to your own choice and your best response to each. The chapter deliberately takes no position; you are being asked to take one and to argue it honestly.
AC. A company obtains approval for a genuinely novel antibiotic and then fails financially. Explain how both of those things can be true at once, and name the feature of good clinical practice that contributes to the outcome.
AD. † Antimicrobial peptides are more expensive to manufacture than most small-molecule antibiotics. Suppose that problem were solved tomorrow and peptide manufacturing cost fell by a factor of ten. Write 300–500 words on what would and would not change about the analysis in this chapter. Be specific about which obstacle each of your claims addresses.
Part 5 — Reading and writing about the field
AE. † Find one popular article about antimicrobial peptides — news, magazine, or a company's own description of its pipeline. Annotate it against this chapter: mark every place it states the strong version of the resistance claim, every place it omits the selectivity problem, every place it treats "peptide antibiotics" as a future technology, and every place it is accurate and well qualified. Submit the annotation with a one-paragraph verdict on the piece as a whole.
AF. † Write two paragraphs on antimicrobial peptides for a general audience. The first must be written to make the field sound as promising as the evidence honestly allows. The second must be written to make it sound as disappointing as the evidence honestly allows. Neither may contain a false statement. Then write a third paragraph identifying which techniques you used in each, and which of those techniques you have seen used in real coverage.
AG. Rewrite this sentence so that it is accurate: "Antimicrobial peptides don't work as drugs yet." Then explain, in two sentences, what the original sentence gets wrong and why the error is common.
AH. † Take one compound from your Evidence Dossier — any compound, not necessarily an antimicrobial one — and audit its Field 11 entry against the five components in this chapter's dossier section. Rewrite the entry to satisfy all five. Then note, in one sentence, which component your original entry was missing, and consider whether the same component is missing from your other entries.