Chapter 25 — Further Reading

Antimicrobial Peptides: The Natural Weapons That Could Solve Antibiotic Resistance

Sources are grouped by what they cost you in effort and what they give you back. Tier 1 is accessible to any careful reader. Tier 2 assumes some comfort with the primary literature. Tier 3 is for people who intend to work in or near the field.

A note on searching this literature: the term "antimicrobial peptide" and the term "host defense peptide" retrieve overlapping but non-identical sets of papers, and the second is more common where immunomodulatory activity is the focus. Search both.

Tier 1 — Start here

The Global Burden of Disease analysis of bacterial antimicrobial resistance for 2019. Published in The Lancet in 2022 by the Antimicrobial Resistance Collaborators. Read at minimum the summary and the discussion of limitations. This is the source of the 1.27 million attributable and 4.95 million associated figures, and reading the two definitions in the authors' own words is the fastest inoculation against misquoting them. Pay attention to the uncertainty intervals and to what the authors say about data availability in the regions carrying the greatest burden.

A general review of antimicrobial peptides as therapeutic candidates, of which many exist in journals such as Nature Reviews Drug Discovery, Nature Reviews Microbiology, and Pharmacological Reviews. Choose one published within the last five years — the field's assessment of its own obstacles has changed, and older reviews are systematically more optimistic about timelines. When you read one, mark every place the review names the selectivity problem. A review that does not is not a good review.

Any current national or international report on antimicrobial resistance, such as those issued periodically by the World Health Organization or by national public health agencies. These are written for policy audiences, they are readable, and they give you the surveillance picture that individual papers cannot.

The O'Neill Review on Antimicrobial Resistance final report (2016). The most influential statement of the economic argument, and the origin of the market-entry-reward proposal discussed in §25.6. It is written for a general audience and is worth reading even if you disagree with its recommendations, because it defines the terms in which the policy debate is now conducted.

Coverage of the pexiganan trials. Search for reporting around the 1999 FDA advisory committee review and around the 2016 Phase 3 results. Reading contemporaneous coverage of a failure is unusually instructive, because you can watch the framing shift between the announcement and the retrospective.

Tier 2 — For readers going deeper

Zasloff's original 1987 report of magainins in Proceedings of the National Academy of Sciences. Short, clear, and a model of how an observation becomes a research program. Read it for the reasoning rather than the data.

Primary literature on AMP mechanism. Look for biophysical work on the barrel-stave, toroidal pore, and carpet models — solid-state NMR, neutron scattering, and single-vesicle leakage studies. This is where the "different peptides use different mechanisms" conclusion comes from, and the papers are more careful about it than the reviews that summarize them.

The 2015 report of mcr-1 in The Lancet Infectious Diseases. Read it alongside any of the follow-up surveillance papers published in the two years after, which document the gene's international spread. Together they make the resistance argument of §25.3 concrete in a way no review does.

Reviews of bacterial resistance mechanisms against host defense peptides. These cover surface charge modification, the regulatory systems that sense peptide presence, efflux, and proteolytic degradation. If you read only one thing beyond the chapter on this topic, make it this — it is the literature that most directly contradicts the popular framing.

Clinical reviews of colistin and of polymyxin pharmacology. Substantial work has been done on colistin's pharmacokinetics and toxicity since its revival, much of it correcting assumptions carried over from the 1960s. Note as you read how much of the modern evidence base was generated after the drug returned to use — a striking illustration of how a drug can be in clinical use for decades without ever having been characterized to modern standards.

Reviews of daptomycin, particularly on its calcium dependence and its inactivation by pulmonary surfactant. The surfactant story is well documented and is one of the cleanest available case studies in site-of-action pharmacology.

Analyses of the antibiotic market failure in health policy and health economics journals. Look for work on delinkage models, subscription procurement pilots, and post-approval commercial outcomes for recently approved antibacterials. This literature is small, empirical, and unusually candid.

Tier 3 — For people working in the field

The antimicrobial peptide databases. Several curated collections catalog sequences, source organisms, activity data, and structural information. They are the standard entry point for sequence-level work. Approach the activity data with the caution §25.5 recommends: assay conditions vary enormously between the underlying papers, and MIC values from different laboratories are often not comparable.

Methodological literature on susceptibility testing and hemolysis assays. Standardized broth microdilution methods exist and are not always followed in AMP papers; media composition, cation content, and inoculum size all move MIC values substantially. If you plan to compare numbers across papers, read the methods literature first, because much of the apparent disagreement in this field is methodological.

Structure–activity relationship studies on cationic amphipathic peptides, particularly work on tuning charge, hydrophobicity, and helicity to widen the selectivity index. This is the engineering core of the field and the place where movement on the 🔬 rating would first appear.

Peptidomimetic and defensin-mimetic chemistry. Work on non-peptide scaffolds that reproduce the cationic amphipathic architecture while escaping proteolysis and manufacturing cost. Chapter 33 covers the general strategy; the specialist literature here is where it is being tested against this particular problem.

Teixobactin and the culturing methods that found it. The 2015 Nature report and the subsequent synthetic and analog work. Read it as a case study in how a preclinical compound generates expectations, and check the current clinical status before repeating anything said about it in 2015.

Regulatory guidance on antibacterial drug development. Agency guidance documents specify what trial designs and endpoints are acceptable for antibacterial indications, including non-inferiority margins. The pexiganan story is much easier to understand once you have read what a sponsor is actually required to demonstrate.

If you only do one thing

Read the Global Burden of Disease analysis' own definitions of "attributable" and "associated" deaths — and then go and find three articles citing the study and check which figure each one used.

It will take you under an hour. You will find sources that used the larger number without qualification, sources that used the smaller one correctly, and probably at least one that used the larger number while describing it in the language of the smaller.

That exercise teaches the skill this chapter is built on better than any amount of reading about peptides. A field's honesty is visible in how it handles its own headline number, and once you have watched a single statistic get mishandled in real time, you will never again accept a figure without asking what it counts.