# Polypeptide antibiotic
A polypeptide antibiotic is an antibiotic whose active molecule is a peptide chain, usually synthesized non-ribosomally by bacteria, that kills or inhibits bacteria by attacking the cell wall or cell membrane. The clinically important members are bacitracin, which blocks cell wall synthesis in gram-positive bacteria, and the polymyxins colistin (polymyxin E) and polymyxin B, which disrupt the outer membrane of gram-negative bacteria[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). The class also includes agents such as the gramicidins and glycopeptides, and, more broadly, actinomycin among antitumor antibiotics[2](https://journals.asm.org/doi/full/10.1128/aac.43.6.1317) • [3](https://uomus.edu.iq/img/lectures21/MUCLecture_2023_4142179.pdf).
| Key fact | Detail |
|---|---|
| Class members in clinical use | Bacitracin, colistin (polymyxin E), and polymyxin B[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) |
| Mechanisms | Bacitracin inhibits cell wall synthesis; colistin and polymyxin B bind anionic lipopolysaccharide and disrupt the gram-negative outer membrane[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) |
| Spectrum | Bacitracin: gram-positive bacteria. Polymyxins: most facultative and aerobic gram-negative bacilli, including Pseudomonas aeruginosa and Acinetobacter species[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) |
| Route | Polypeptides other than colistin are usually topical, with negligible systemic absorption; colistin and polymyxin B are given intravenously for serious resistant infections[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) • [4](https://www.msdmanuals.com/home/infections/antibiotics/polypeptides) |
| Main toxicity | Nephrotoxicity and central and peripheral neurotoxicity with the polymyxins; minimal toxicity with topical bacitracin[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) |
| Resistance | Lipid A modification of lipopolysaccharide; plasmid-borne mcr-1, 2, and 3 genes; cross-resistance between colistin and polymyxin B is nearly 100%[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) |
| Regulatory status | The Clinical and Laboratory Standards Institute has removed all "susceptible" breakpoints for the polymyxins and endorses only "intermediate" as the lowest breakpoint[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) |
## Members and chemical nature
The class is chemically diverse, containing non-protein polypeptide chains, and its members differ widely in mechanism and antimicrobial properties[3](https://uomus.edu.iq/img/lectures21/MUCLecture_2023_4142179.pdf). Most are made non-ribosomally on multienzyme complexes rather than on ribosomes, a biosynthetic route that allows unusual amino acids, D-amino acids, N-methylation, acylation, glycosylation, and heterocyclic ring formation in the final product[2](https://journals.asm.org/doi/full/10.1128/aac.43.6.1317). Bacitracin, gramicidin S, and polymyxin B are the structures used clinically among the classical peptide antibiotics[2](https://journals.asm.org/doi/full/10.1128/aac.43.6.1317).
The polymyxins are cationic cyclic polypeptides consisting of a cyclic heptapeptide with a tripeptide side chain acylated at the N terminus by a fatty acid tail; their structure resembles that of cationic antimicrobial peptides such as defensins, part of the innate defense against bacterial colonization[5](https://journals.asm.org/doi/10.1128/CMR.00064-16). Polymyxins A through E are known, but only polymyxin B and polymyxin E (colistin) have been used clinically[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC8082492/).
## Mechanisms of action
**Bacitracin** blocks cell wall construction. It forms a complex with C55-isoprenyl pyrophosphate, a lipid carrier that transfers polysaccharides, peptidoglycan, and lipopolysaccharide building blocks to the growing wall, so that wall formation is stunted[7](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic). Its activity is primarily against gram-positive organisms: staphylococci, streptococci, corynebacteria, and clostridia[7](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic).
**Colistin and polymyxin B** are cationic, so they bind the anionic lipopolysaccharide (endotoxin) of the gram-negative outer membrane, disrupting the membrane, neutralizing the bacteria's toxicity, and causing cell death[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). They show rapid, exposure-dependent bactericidal activity in vitro, with the AUC/MIC ratio best predicting killing[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Debate remains over the precise mode of killing, and significant gaps in understanding how these drugs kill bacteria persist[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC8941995/).
## Clinical use
Bacitracin is used mainly as a topical treatment for superficial skin infections caused by [Staphylococcus aureus](https://www.edgepedia.org/staphylococcus-aureus)[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). It is often formulated with neomycin, polymyxin B, or both, in ointments for wound infection and in ophthalmic and otic preparations[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) • [7](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic). Its efficacy in controlled clinical trials has never been shown: in impetigo it cleared pathogenic organisms in 80% of patients but failed in six of nine patients in a trial against topical mupirocin or oral cephalexin, and it was least effective in bullous impetigo[7](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic).
The polymyxins are active against most facultative and aerobic gram-negative bacilli, including [Pseudomonas aeruginosa](https://www.edgepedia.org/pseudomonas-aeruginosa) and [Acinetobacter](https://www.edgepedia.org/acinetobacter) species, but not against Proteus, Providencia, Burkholderia, and Serratia species, some obligate anaerobes including [Bacteroides fragilis](https://www.edgepedia.org/bacteroides-fragilis), or gram-positive bacteria[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Because they commonly cause kidney damage, colistin and polymyxin B are reserved for serious infections in which bacteria are resistant to all other antibiotics and no safer alternatives exist[4](https://www.msdmanuals.com/home/infections/antibiotics/polypeptides). Newer beta-lactam plus inhibitor combinations are preferable to polymyxin-based therapy whenever possible[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b).
**Formulations and dosing.** [Colistin](https://www.edgepedia.org/colistin) is given intravenously as colistimethate sodium (CMS), a prodrug converted in blood and urine to colistin; CMS is less toxic than colistin[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Aerosolized CMS and colistin sulfate are used in cystic fibrosis and occasionally for hospital-acquired pneumonia caused by multidrug-resistant gram-negative bacilli[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). [Polymyxin B](https://www.edgepedia.org/polymyxin-b) solutions are also used for genitourinary irrigation and bladder irrigation[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b) • [4](https://www.msdmanuals.com/home/infections/antibiotics/polypeptides). Because colistin predates modern pharmacokinetic analysis, dosing is not standardized: manufacturers describe amounts variously in international units, milligrams of colistin base activity, or milligrams of colistimethate, and many experts consider the manufacturer-recommended dose of 2.5 to 5 mg/kg of colistin base activity per day in 2 to 4 divided doses too low, though nephrotoxicity is dose-dependent and rises with higher doses[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b).
## Resistance
Resistance to colistin and polymyxin B is typically acquired through modifications to the lipid A moiety of lipopolysaccharide that make the cell surface more positively charged, removing affinity for the positively charged drugs[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Acquired resistance can be carried on mobile genetic elements, including the mcr-1, mcr-2, and mcr-3 (mobilized colistin resistance) plasmid genes, which raise the risk of horizontal transfer between bacteria[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Cross-resistance between colistin and polymyxin B is nearly 100%[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Additional reported mechanisms include binding to anionic capsular polysaccharide in [Klebsiella pneumoniae](https://www.edgepedia.org/klebsiella-pneumoniae) and efflux pumps[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10019944/pdf/nihms-1881758.pdf). Resistance to bacitracin is rare, although it has been reported in S. aureus[7](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic).
## Toxicity and limitations
Adverse effects of the class include nephrotoxicity and central and peripheral neurotoxicity[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). A systematic review estimated an overall nephrotoxicity rate of 28.1% (95% CI 25.9 to 30.7) in patients treated with polymyxin B or CMS[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10019944/pdf/nihms-1881758.pdf). CMS and polymyxin B may cause circumoral and extremity paresthesias, vertigo, slurred speech, and muscle weakness with respiratory difficulty from neuromuscular blockade, especially with renal insufficiency[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). They should not be given simultaneously with neuromuscular blockers such as rocuronium or nephrotoxic drugs such as aminoglycosides when avoidable[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Other reported effects include skin hyperpigmentation, pulmonary toxicity, and immunotoxicity[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC10019944/pdf/nihms-1881758.pdf).
Comparative evidence favors polymyxin B over colistin on kidney safety: a meta-analysis of 22 observational trials found lower nephrotoxicity with polymyxin B than with colistin (odds ratio 0.58, 95% CI 0.36 to 0.93), while mortality was higher in the polymyxin B group than in controls[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC11165566/). Because of poor clinical outcomes, high toxicity, and unreliable MIC testing methods, the [Clinical and Laboratory Standards Institute](https://www.edgepedia.org/clinical-and-laboratory-standards-institute) has removed all "susceptible" breakpoints for the polymyxins and endorses only "intermediate" as the lowest breakpoint[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b). Poor lung activity means the polymyxins should not be considered for treatment of pneumonias[1](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b).
Topical bacitracin is generally well tolerated, with minor skin irritation and occasional allergic contact dermatitis; rare cases of anaphylaxis have followed topical application to open lesions, intraoperative irrigation, and use with nasal packing after rhinoplasty, apparently requiring access to the systemic circulation[7](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic).
## History
Bacitracin was isolated in 1945 from [Bacillus subtilis](https://www.edgepedia.org/bacillus-subtilis) and [Bacillus licheniformis](https://www.edgepedia.org/bacillus-licheniformis) and was approved by the FDA in 1948 for short-term prevention and treatment of localized skin infections[11](https://pubs.rsc.org/en/content/articlepdf/2021/cs/d0cs00729c). Columbia University scientists identified it in 1945 and named it after a patient whose wound culture yielded the producing bacterium[12](https://cen.acs.org/articles/91/i36/Antibacterial-History.html). The first polymyxin peptide antibiotic was discovered in 1947, and colistin itself was isolated in 1949; despite kidney toxicity, colistin is often used today as a last resort against multidrug-resistant bacteria[12](https://cen.acs.org/articles/91/i36/Antibacterial-History.html). Colistin was originally obtained from the soil bacterium [Paenibacillus polymyxa](https://www.edgepedia.org/paenibacillus-polymyxa) subsp. colistinus[5](https://journals.asm.org/doi/10.1128/CMR.00064-16). The polymyxins regained significant interest as infections caused by multidrug-resistant gram-negative bacteria increased, and they are seriously reconsidered as last-resort antibiotics in areas where multidrug resistance is common[5](https://journals.asm.org/doi/10.1128/CMR.00064-16). Among the related lipopeptides, daptomycin is the only one approved for clinical use, alongside the two polymyxins available for human treatment[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC8941995/).
## References
1. [Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B, Merck Manual Professional Edition](https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/polypeptide-antibiotics-bacitracin-colistin-polymyxin-b)
2. [Peptide Antibiotics, Antimicrobial Agents and Chemotherapy](https://journals.asm.org/doi/full/10.1128/aac.43.6.1317)
3. [Pharmacognesy III lecture notes, University of Mosul](https://uomus.edu.iq/img/lectures21/MUCLecture_2023_4142179.pdf)
4. [Polypeptides, MSD Manual Consumer Version](https://www.msdmanuals.com/home/infections/antibiotics/polypeptides)
5. [Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes, Clinical Microbiology Reviews](https://journals.asm.org/doi/10.1128/CMR.00064-16)
6. [The safety of polymyxin antibiotics, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8082492/)
7. [Polypeptide Antibiotic overview, ScienceDirect Topics](https://www.sciencedirect.com/topics/immunology-and-microbiology/polypeptide-antibiotic)
8. [Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8941995/)
9. [Pharmacokinetics and pharmacodynamics of peptide antibiotics, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10019944/pdf/nihms-1881758.pdf)
10. [Efficiency of polymyxin B treatment against nosocomial infection: a systematic review and meta-analysis, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11165566/)
11. [The multifaceted nature of antimicrobial peptides, Chem Soc Rev](https://pubs.rsc.org/en/content/articlepdf/2021/cs/d0cs00729c)
12. [Antibacterial History, C&EN](https://cen.acs.org/articles/91/i36/Antibacterial-History.html)
---
*Topic: Encyclopedia › Life and health › Biological foundations › Development and comparative physiology › Cellular, regenerative, and comparative physiology › Teratology and embryotoxicity › Teratogens and teratogenic agents*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license