Antimicrobial peptides kill by physically disrupting the bacterial membrane rather than by inhibiting a single enzyme. That mechanism explains both why resistance is slow to appear and why development is unusually hard.
The mechanism
Most AMPs are short, cationic and amphipathic: a positive net charge attracted to the anionic bacterial surface, and a face of hydrophobic residues that inserts into the lipid bilayer. Bacterial membranes are rich in anionic phospholipids and, in Gram-negatives, wrapped in lipopolysaccharide, while mammalian outer leaflets are largely zwitterionic and contain cholesterol. That difference is the entire basis of selectivity.
Once bound, the accepted models describe barrel stave pores, toroidal pores or a carpet mechanism in which the peptide accumulates until the membrane loses integrity. Several AMPs also have intracellular targets once they get in, but membrane disruption is the primary event.
Why resistance is slower
Escaping a peptide that attacks the membrane means changing the membrane, which is expensive. Bacteria do it: modifying lipid A with phosphoethanolamine or aminoarabinose to reduce net negative charge, altering phospholipid composition, or producing proteases. But there is no single point mutation that abolishes binding the way a target mutation abolishes an enzyme inhibitor, so the frequency of resistance is generally low.
The exception proves the rule. Plasmid borne mcr-1 encodes exactly such a lipid A modification against colistin, and because it is plasmid borne it moves between organisms. Slow to appear is not the same as never.
The ones already in clinical use
- Polymyxins, including colistin (polymyxin E). Cyclic lipopeptides that bind lipid A and permeabilise the outer membrane. Reserved because of nephrotoxicity, and still important against carbapenem resistant Gram-negatives.
- Daptomycin, a calcium dependent lipopeptide acting on Gram-positive membranes. Inactive in the lung because pulmonary surfactant sequesters it, which is a good example of how membrane activity creates unusual failure modes.
- Gramicidin and bacitracin, topical only, largely for toxicity reasons.
The liabilities, stated honestly
| Liability | Why it happens | What programs do about it |
|---|---|---|
| Haemolysis and cytotoxicity | The same amphipathicity acts on mammalian membranes | Optimise the therapeutic index, measure it early and often |
| Protease degradation | Peptides are substrates for host and bacterial proteases | D-amino acids, cyclisation, peptidomimetics |
| Serum and salt sensitivity | Divalent cations and serum proteins compete with binding | Assay in physiological conditions, not just in low salt buffer |
| Poor oral exposure | Size and charge | Topical, inhaled or intravenous routes |
| Cost of goods | Peptide synthesis at scale | Shorter sequences, fermentation, mimetics |
A common pattern in AMP papers is a peptide with an impressive MIC in low salt buffer and much weaker activity in physiological conditions. When reading published activity for an AMP series, the assay conditions matter as much as the number, which is a general point covered under minimum inhibitory concentration.
Screening an AMP series
Two things are worth knowing before you run one:
- Confidence will often be lower. The published neighbourhood for a novel peptide sequence is thinner than for a small molecule scaffold, and the honest output is a low confidence row rather than a confident number.
- The mechanism reasoning is still useful. Charge, amphipathicity and the presence of lipid A modifications in the target organism drive the call, and those are exactly the features a per strain read-out can talk about.
The screen below is preselected with colistin as a reference point. Replace it with your own sequence or structure and compare. For the alternative non chemical route to the same organisms, see phage therapy.