Antimicrobial peptides: the antibiotic pipeline's long shot

Why they looked like the answer

Antimicrobial peptides are part of almost every organism's defence, and they kill bacteria by a route conventional antibiotics mostly do not use: disrupting the cell membrane rather than inhibiting an enzyme or a ribosome. That gives them broad activity, including against drug-resistant strains, and a mechanism resistance was expected to find harder to evade. Thousands have been described, and most kill a wide range of bacteria at reasonable concentrations in a dish.

Translating that into a medicine turned out to be a different problem. Human trials of antimicrobial peptides are a long list of near misses, and the few that became drugs are used when little else works.

The two that worked

Daptomycin is a cyclic lipodepsipeptide approved in the United States in 2003 as Cubicin, for complicated skin infections and later for Staphylococcus aureus bloodstream infection, with generics since 2021 ¹. A 2025 review describes it as a mainstay for serious Gram-positive infections, including methicillin-resistant S. aureus and vancomycin-resistant enterococci, and one of the last-resort antibiotics for life-threatening infections that do not respond to first-line treatment, while noting that resistance is eroding its efficacy (review) ². In its pivotal trial in 246 patients with S. aureus bloodstream infection, success at 42 days was 44.2% with daptomycin against 41.7% with standard therapy (randomised trial) ³.

The polymyxins, colistin and polymyxin B, are older. A 2022 review sets out how the two classes differ despite similar structures: the polymyxins target lipopolysaccharide in Gram-negative membranes and are used against carbapenem-resistant organisms such as Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa, while daptomycin requires membrane phosphatidylglycerol and is used only against Gram-positives (review) ⁴. Both disrupt membranes, are potently bactericidal in the laboratory, and share resistance mechanisms ⁴.

What last resort costs

The polymyxins are used despite their toxicity, not because they lack it. A meta-analysis of five randomised trials with 377 patients, most receiving colistin for pneumonia in intensive care, found kidney toxicity in 36.2% of those given colistin, significantly more than comparators, with a relative risk of 2.40 (meta-analysis) ⁵. These are the drugs reached for when carbapenems have failed, and the calculation is made with that in mind: a one-in-three risk of kidney injury is acceptable against an infection that would otherwise be untreatable, and nowhere else.

Daptomycin carries a different limitation that is instructive about peptides generally. It failed to meet non-inferiority criteria in a trial in severe community-acquired pneumonia, and the reason was found in the laboratory: daptomycin interacts with pulmonary surfactant, which inhibits its antibacterial activity; it worked in bloodstream-origin pneumonia and inhalation anthrax in animals but not against pneumococcus in simple bronchial-alveolar pneumonia (laboratory and animal study) ⁶. A membrane-active peptide is at the mercy of whatever else is in the environment it meets.

The failures, and what they have in common

The clearest run of failures is in oral mucositis, the mouth ulceration caused by cancer treatment, where the theory was that bacteria contribute. Iseganan, an analogue of the pig peptide protegrin-1, was tested twice. In 545 patients receiving radiotherapy for head and neck cancer, 9% of patients in both the iseganan and placebo groups avoided ulcerative mucositis (p = 0.998), while only 2% did on standard care alone (randomised trial) ⁷. In 502 patients receiving stomatotoxic chemotherapy, patients rinsed with iseganan or placebo six times daily for up to 21 days, and the primary endpoint was the proportion avoiding moderate or worse stomatitis (randomised trial) ⁸. Neither trial changed practice, and iseganan was not approved.

Pexiganan, an analogue of a frog peptide, was tested as a cream in 835 patients with mildly infected diabetic foot ulcers against an oral antibiotic: one of the two phase 3 trials failed to show equivalence, while the other and the combined data showed similar clinical improvement, around 85% to 90%, and similar pathogen eradication; it was not approved (randomised trials) ⁹. Omiganan's catheter-infection programme missed its endpoints, and its later dermatology trials were mixed, as our acne and rosacea guide describes ¹.

Even the body's own peptide has struggled. In HEAL LL-37, a phase 2b trial in 148 patients with hard-to-heal venous leg ulcers, LL-37 at two concentrations alongside compression showed no significant improvement in healing against placebo on the full study population, though a post hoc analysis found differences on several related healing measures (randomised trial) ¹⁰.

The mucositis programme is the most instructive of the set, because the peptide was doing its job. Iseganan is microbicidal, it was delivered straight to the tissue in question, and it still changed nothing, which suggests the premise, that oral bacteria drive the ulceration, was the weak link rather than the drug ⁷.

A pattern runs through these. The peptides killed the organisms. What they failed to do was change the clinical outcome the trial measured, because the outcome depended on more than the bacteria, or because the peptide did not survive the environment it was placed in.

Why translation is so hard

Several obstacles recur. Peptides are broken down by the proteases abundant in human tissue and blood, which is why so many of them are developed as topical rather than systemic treatments. They bind to proteins and surfaces, so the concentration that works in a clean dish is not the concentration present at the target. Their membrane activity is not perfectly selective, which sets a ceiling on the systemic dose. And manufacturing a peptide at the scale and cost of an antibiotic is harder than making a small molecule, as our manufacturing guide explains.

Resistance has also proved less impossible than hoped. The 2022 review notes that the polymyxins and lipopeptides share resistance mechanisms despite their distinct targets ⁴, and the daptomycin review records resistance eroding clinical efficacy over two decades of use ².

What is still being tried

The newer attempts mostly change the molecule rather than the idea. Murepavadin is a peptidomimetic, a designed molecule based on a peptide, that acts on a single target, the LptD protein in the outer membrane of Pseudomonas aeruginosa, rather than disrupting membranes indiscriminately. A 2018 review described it as a new antibiotic class in phase 3 development for hospital-acquired and ventilator-associated pneumonia caused by P. aeruginosa (review) ¹¹. It is still being studied in the laboratory, including against biofilms and in combination with conventional antibiotics (laboratory study) ¹². We did not find a published report of its phase 3 results, so this page does not describe an outcome.

The shift that murepavadin represents is worth noting: from the broad, membrane-disrupting activity that made antimicrobial peptides attractive, towards a specific molecular target, which is how conventional antibiotics work. Other current approaches include delivering peptides locally, combining them with existing antibiotics to delay resistance, and designing protease-resistant forms such as mirror-image peptides.

Where they do earn their place

Two uses show what works. Bacitracin, a peptide antibiotic, is an over-the-counter topical in first-aid ointments, where delivery is direct and the dose is local ¹. Nisin, a bacteriocin, is not a drug at all: it is affirmed as generally recognised as safe for a food use in the US food regulations ¹. Topical and local applications sidestep most of the problems above, which is also why most antimicrobial peptides still in development are being tested on skin, in wounds or in the mouth rather than injected. Nisin's regulatory history also shows how differently the same molecule is treated by purpose: a food preservative clears a different bar from an injected drug, and the entry on it records which one it has cleared ¹.

What this means for peptides sold online

None of this makes antimicrobial peptides sold as research chemicals into treatments. LL-37 is on FDA's list of bulk substances that may present significant safety risks, with concerns about immunogenicity and impurities, and it is the subject of a compounding advisory committee agenda item for a meeting FDA has said will be held before the end of February 2027 ¹. Our LL-37 guide sets out what its trials found. Buying a peptide because it kills bacteria in a laboratory is exactly the inference the trials above tested and mostly refuted.

The bottom line

Antimicrobial peptides produced two classes of important drugs, both reserved for infections that have defeated everything else, and both with real costs: kidney injury for the polymyxins, inactivation by surfactant and creeping resistance for daptomycin. Everything else that reached a large trial, iseganan twice, pexiganan partly, omiganan, LL-37, failed to show the benefit its laboratory activity promised. The field is not dead, but its record is the reason new candidates are mostly topical.

Frequently asked questions

Are antimicrobial peptides used as antibiotics?

Yes, two classes: daptomycin and the polymyxins (colistin and polymyxin B). Both are reserved for infections resistant to other treatments.

Why do antimicrobial peptides fail in trials?

They are broken down by proteases, bind to proteins and surfaces, are limited by toxicity at systemic doses, and killing bacteria often does not change the outcome a trial measures.

How toxic is colistin?

In a meta-analysis of five randomised trials, kidney toxicity occurred in 36.2% of colistin patients, with a relative risk of 2.40 against comparators.

Why did daptomycin fail in pneumonia?

Pulmonary surfactant inhibits its antibacterial activity, which was shown in laboratory work after the trial missed its non-inferiority criteria.

Is LL-37 a treatment for wounds?

No. In a 148-patient trial in hard-to-heal venous leg ulcers, it showed no significant improvement over placebo on the full study population.

Related on Grey Peptides

• Daptomycin
• Colistin
• LL-37 guide

Sources

1. Grey Peptides encyclopedia entries for daptomycin (Cubicin, NDA 021572, approved September 12, 2003; generics from 2021), colistin (Coly-Mycin M, NDA 050108, 1970), bacitracin (over-the-counter topical), nisin (21 CFR 184.1538 food use), omiganan and LL-37, with the FDA safety-risk list and the compounding advisory committee's 2027 agenda. Drugs@FDA and eCFR read October 1, 2026; FDA pages read October 3, 2026.
2. Taylor, S. D., et al. (2025). Daptomycin: Mechanism of action, mechanisms of resistance, synthesis and structure-activity relationships. Prog Mol Biol Transl Sci, 212, 163-234. PMID: 40122645
3. Fowler VG, J. r., et al. (2006). Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med, 355(7), 653-65. PMID: 16914701
4. Ledger, E. V. K., et al. (2022). Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort. Microbiology (Reading), 168(2). PMID: 35118938
5. Eljaaly, K., et al. (2021). Colistin Nephrotoxicity: Meta-Analysis of Randomized Controlled Trials. Open Forum Infect Dis, 8(2), ofab026. PMID: 33623807
6. Silverman, J. A., et al. (2005). Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact. J Infect Dis, 191(12), 2149-52. PMID: 15898002
7. Trotti, A., et al. (2004). A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy. Int J Radiat Oncol Biol Phys, 58(3), 674-81. PMID: 14967419
8. Giles, F. J., et al. (2004). A phase III, randomized, double-blind, placebo-controlled, study of iseganan for the reduction of stomatitis in patients receiving stomatotoxic chemotherapy. Leuk Res, 28(6), 559-65. PMID: 15120931
9. Lipsky, B. A., et al. (2008). Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis, 47(12), 1537-45. PMID: 18990064
10. Mahlapuu, M., et al. (2021). Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial. Wound Repair Regen, 29(6), 938-950. PMID: 34687253
11. Martin-Loeches, I., et al. (2018). Murepavadin: a new antibiotic class in the pipeline. Expert Rev Anti Infect Ther, 16(4), 259-268. PMID: 29451043
12. Yılmaz, U., et al. (2026). Murepavadin is a novel peptide antibiotic that exhibits potent antibiofilm activity and enhances the efficacy of conventional antibiotics against Pseudomonas aeruginosa. Biofouling, 42(7), 771-781. PMID: 42459059

Educational information, not medical advice. Each dose in this guide names its source, an approved label or a published study. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose.