Chapter 25 — Quiz

Antimicrobial Peptides: The Natural Weapons That Could Solve Antibiotic Resistance

22 items. Answer without referring to the chapter, then check yourself against the key at the bottom. Items 19–22 are short-answer.

1. According to the Global Burden of Disease estimate cited in §25.1, how many deaths were directly attributable to bacterial antimicrobial resistance, and in what year?

  • A. About 700,000 in 2016
  • B. About 1.27 million in 2019
  • C. About 4.95 million in 2019
  • D. About 10 million in 2050

2. The difference between "attributable" and "associated" deaths in that estimate is best described as:

  • A. Two names for the same quantity
  • B. Attributable counts only hospital deaths; associated includes community deaths
  • C. Attributable is the modeled excess caused by resistance; associated is all death occurring with a resistant infection present
  • D. Associated is a lower bound and attributable is an upper bound

3. Antimicrobial peptides are produced by:

  • A. Vertebrates only
  • B. Bacteria only
  • C. Essentially all multicellular organisms, plants and animals alike
  • D. Only organisms that lack adaptive immunity

4. The property that draws an antimicrobial peptide toward a bacterial surface is:

  • A. A specific receptor on the bacterial membrane
  • B. Its net positive charge, attracted to a negatively charged surface
  • C. Hydrogen bonding to peptidoglycan
  • D. Enzymatic recognition of lipid A

5. "Amphipathic" means the peptide:

  • A. Is active against both Gram-positive and Gram-negative organisms
  • B. Can act at two different receptors
  • C. Has spatially segregated hydrophobic and hydrophilic faces
  • D. Is stable at both acidic and alkaline pH

6. Which model describes peptides accumulating flat on the membrane surface until the bilayer breaks up detergent-like, with no discrete pore?

  • A. Barrel-stave
  • B. Toroidal pore
  • C. Carpet
  • D. Lipid II sequestration

7. The chapter's argument for why resistance to AMPs is harder to evolve rests on:

  • A. AMPs being too large for efflux pumps
  • B. Membrane restructuring being a much larger evolutionary change than a single point mutation in a drug target
  • C. Bacteria lacking the genes required to modify surface charge
  • D. AMPs killing too quickly for mutation to occur

8. Which of the following is not a documented bacterial resistance mechanism against antimicrobial peptides?

  • A. Modification of surface charge
  • B. Efflux
  • C. Proteolytic cleavage of the peptide
  • D. Loss of the peptide's binding receptor

9. mcr genes confer resistance to colistin by:

  • A. Pumping colistin out of the cell
  • B. Adding phosphoethanolamine to lipid A, reducing outer-membrane negative charge
  • C. Cleaving the cyclic peptide ring
  • D. Thickening the peptidoglycan layer

10. The single human cathelicidin is:

  • A. hBD-2
  • B. HNP-1
  • C. LL-37
  • D. Magainin 2

11. Magainins were isolated from:

  • A. Human neutrophil granules
  • B. The skin of the African clawed frog
  • C. A soil actinomycete
  • D. Bovine airway epithelium

12. Mammalian plasma membranes resist AMP insertion better than bacterial membranes principally because they:

  • A. Are thicker
  • B. Present mostly zwitterionic phospholipids on the outer leaflet and contain cholesterol
  • C. Lack phospholipids entirely
  • D. Are protected by an outer layer of peptidoglycan

13. The selectivity index is:

  • A. The number of bacterial species a peptide kills
  • B. The ratio of the concentration harming host cells to the concentration killing bacteria
  • C. The proportion of hydrophobic residues in the sequence
  • D. The ratio of in vivo to in vitro potency

14. Two peptides have identical MICs against E. coli. Peptide A has a selectivity index of 64; Peptide B has one of 4. Which statement is correct?

  • A. Peptide A is more potent
  • B. Peptide B is more potent
  • C. They are equally potent against bacteria, but only Peptide A has a plausible systemic future
  • D. Neither could be used topically

15. The reason a new antibiotic is commercially unattractive includes all of the following except:

  • A. It is taken for days rather than years
  • B. Good stewardship deliberately restricts its use
  • C. Resistance erodes its value over time
  • D. Regulators refuse to grant patents on antibacterial agents

16. Colistin was largely abandoned in the 1970s and 1980s because of:

  • A. Loss of activity against Gram-negatives
  • B. Nephrotoxicity and neurotoxicity, alongside better-tolerated alternatives
  • C. Manufacturing failure
  • D. Withdrawal of its approval

17. Daptomycin is not used for pneumonia because:

  • A. It cannot reach lung tissue
  • B. It is inactivated by pulmonary surfactant
  • C. It is active only against Gram-negative organisms
  • D. It causes bronchospasm

18. In this book's rating system, the difference between ❌ and 🔬 is best stated as:

  • A. ❌ means the drug does not work; 🔬 means it might
  • B. ❌ means animal data only; 🔬 means human data only
  • C. ❌ is a judgment about a confident claim that has outrun its evidence; 🔬 describes a field proceeding properly with no verdict yet available
  • D. ❌ is permanent; 🔬 is temporary

Short answer

19. State the chapter's rating for "antimicrobial peptides as broad-spectrum systemic antibiotics," and give the four elements the chapter says justify it.

20. In no more than three sentences, correct the statement: "Antimicrobial peptides have never worked as drugs."

21. Explain why topical AMP applications have progressed further in development than systemic ones. Your answer must refer to the selectivity problem.

22. Write the "what would change it" line for a 🔬 rating on a systemic AMP-derived antibiotic. It must be bidirectional and must name at least one safety endpoint.

Answer key **1. B.** Approximately 1.27 million deaths directly attributable, for the year 2019. The associated figure — about 4.95 million — is the one more often quoted without qualification. **2. C.** Attributable is the modeled excess: deaths that would not have occurred had the organism been susceptible rather than resistant. Associated counts deaths in which a resistant infection was present in the causal chain at all. Neither is "wrong"; they answer different questions, and a source that does not say which it is using does not know. **3. C.** AMPs are near-universal across multicellular life. Adaptive immunity is the recent, vertebrate-restricted system; innate immunity, including AMPs, is far older and far more widely distributed. **4. B.** Electrostatic attraction between the cationic peptide and the anionic bacterial surface. There is no receptor — which is the whole point of the contrast with Chapter 2. **5. C.** Segregated hydrophobic and hydrophilic faces. In an α-helical AMP this arises because residues spaced three or four apart in sequence land on the same side of the helix. **6. C.** The carpet model. Barrel-stave forms a discrete peptide-lined channel; toroidal pore forms a pore lined by both peptide and lipid headgroups. **7. B.** A point mutation alters one protein; resisting a membrane-disrupting agent requires changing the composition or architecture of the membrane itself, which is a much larger evolutionary ask. **8. D.** There is no receptor to lose — that is the mechanism's distinguishing feature. A, B, and C are all documented, along with capsule and biofilm shielding. **9. B.** Phosphoethanolamine addition to lipid A reduces the outer membrane's negative charge and so weakens the electrostatic attraction colistin depends on. Because *mcr* sits on a plasmid, it can move horizontally between organisms. **10. C.** LL-37. Humans have exactly one cathelicidin; the name describes the molecule — two leucines, 37 residues. **11. B.** *Xenopus laevis* skin, described in 1987, after the observation that frogs with surgical wounds in non-sterile water did not develop infections. **12. B.** Zwitterionic (net neutral) outer-leaflet phospholipids and cholesterol, which increases bilayer ordering and rigidity. Note that this is a difference of degree, not kind. **13. B.** Higher is better. It is the field's therapeutic window and the metric on which most candidates fail. **14. C.** Identical MIC means identical antibacterial potency. A paper reporting only MIC would present them as equivalent discoveries; the number that separates them is not in the antibacterial data at all. **15. D.** Patents are available on antibacterial agents, and companies have taken proprietary AMPs into Phase 3. The other three are all real features of the market failure. **16. B.** Toxicity plus better-tolerated alternatives. Nothing about the drug changed when it returned; the alternative got worse. **17. B.** Pulmonary surfactant binds and neutralizes it. Daptomycin works elsewhere in the body and is defeated by the biochemistry of one organ — a clean illustration that a drug's effect depends on what happens to it at the site of action. **18. C.** Both mean "we don't know," but only one of them is somebody's fault. ❌ points at an assertion; 🔬 describes a stage. **19.** 🔬 Frontier. The four elements: (i) a real, biophysically demonstrated mechanism; (ii) real obstacles clearly identified by the field itself — selectivity margin, host-factor inactivation, manufacturing cost, antibiotic economics; (iii) real programs, including compounds that reached Phase 3; (iv) no verdict available, since no systemic agent from this lineage has been approved. **20.** Peptide antibiotics have worked as drugs for over sixty years — colistin, daptomycin, vancomycin, bacitracin, polymyxin B, and gramicidin are all peptides in approved use. What has not yet succeeded is the narrower project of converting the host defense peptides of innate immunity into new broad-spectrum systemic antibiotics. That project has produced no approved agent, for reasons that are partly biological (selectivity) and partly economic. **21.** Because a topical agent faces a much lower selectivity bar. The exposed tissue volume is small and defined; systemic absorption across skin is low; and the adverse effect being risked is local irritation rather than acute kidney injury. The pattern in the development pipeline is the selectivity index expressing itself in the structure of the field. **22.** A model answer: *Upward — a randomized controlled trial of a systemic AMP-derived agent in a defined infection showing efficacy at least comparable to standard care, with acceptable renal function and hemolysis endpoints, would move this to ⚠️; approval plus consistent post-marketing use would move it to ✅. Downward — repeated Phase 3 halts for toxicity across structurally distinct candidates, or a demonstration that the selectivity margin cannot be widened in humans by any available strategy, would move it toward ❌ for the systemic claim, leaving topical and immunomodulatory claims untouched.* Credit requires a named safety endpoint and both directions.