Polymyxins are a class of antibiotics that were discovered in 1947 from programs searching for compounds effective in the treatment of Gram-negative infections. Produced by the Gram-positive bacterium Paenibacillus polymyxa and composed of a cyclic peptide chain with a peptide-fatty acyl tail, polymyxins exert bactericidal effects through membrane disruption. Currently, polymyxin B and colistin (polymyxin E) have been developed for clinical use, where they are reserved as “last-line” therapies for multidrug-resistant (MDR) infections. Unfortunately, the incidences of strains resistant to polymyxins have been increasing globally, and polymyxin heteroresistance has been gaining appreciation as an important clinical challenge. These phenomena, along with bacterial tolerance to this antibiotic class, constitute important contributors to polymyxin treatment failure. Here, we review polymyxins and their mechanism of action, summarize the current understanding of how polymyxin treatment fails, and discuss how the next generation of polymyxins holds promise to invigorate this antibiotic class.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Benedict RG, Langlykke AF. Antibiotic activity of Bacillus polymyxa. J Bacteriol. 1947;54:24.
Ainsworth GC, Brown AM, Brownlee G. Aerosporin, an antibiotic produced by Bacillus aerosporus greer. Nature 1947;159:263.
Stansly PG, Shepherd RG, White HJ. Polymyxin: a new chemotherapeutic agent. Bull Johns Hopkins Hosp. 1947;81:43–54.
Fleming A. On the antibacterial action of cultures of a Penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol. 1929;10:226–36.
Velkov T, Thompson PE, Azad MAK, Roberts KD, Bergen PJ. History, Chemistry and Antibacterial Spectrum. In:Li J, Nation RL, Kaye KS, editors. Polymyxin antibiotics: from laboratory bench to bedside, Vol 1145. Cham, Switzerland: Springer International Publishing; 2019. p. 15–36.
WHO. World Health Organization Model List of Essential Medicines – 22nd List, 2021. 2021. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02
FDA. FDA Approved Drug Products. Label and approval history for Coly-Mycin M, NDA 050108. 2017. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=050108.
Nation RL, et al. Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform? Clin Infect Dis. 2015;62:552–8.
Zavascki AP, Goldani LZ, Li J, Nation RL. Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother. 2007;60:1206–15.
Levin AS, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis. 1999;28:1008–11.
Markou N, et al. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Crit Care. 2003;7:R78–83.
Garnacho-Montero J, et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis. 2003;36:1111–8.
Lu L-C, Chang F-Y, Lv G-Z, Lan S-H. Effectiveness and Safety of Compound Polymyxin B Ointment in Treatment of Burn Wounds: A Meta-analysis. J Burn Care Res. 2021;43:453–61.
Johansen HK, Moskowitz SM, Ciofu O, Pressler T, Høiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. J Cyst Fibros. 2008;7:391–7.
Arduino SM, et al. 2012. Transposons and integrons in colistin-resistant clones of Klebsiella pneumoniae and Acinetobacter baumannii with epidemic or sporadic behaviour. J Med Microbiol. 2012;61:1417–20.
Mammina C, et al. Ongoing spread of colistin-resistant Klebsiella pneumoniae in different wards of an acute general hospital, Italy, June to December 2011. Eur Surveill. 2012;17:20248.
Thet KT, et al. Colistin heteroresistance in carbapenem-resistant Acinetobacter baumannii clinical isolates from a Thai university hospital. World J Microbiol Biotechnol. 2020;36:102.
Hong Y-K, Kim H, Ko KS. Two types of colistin heteroresistance in Acinetobacter baumannii isolates. Emerg Microbes Infect. 2020;9:2114–23.
Howard-Anderson J, et al. Prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa and association with clinical outcomes in patients: an observational study. J Antimicrob Chemother. 2022;77:793–8.
Lin J, et al. Resistance and Heteroresistance to Colistin in Pseudomonas aeruginosa Isolates from Wenzhou, China. Antimicrob Agents Chemother. 2019;63:e00556–19.
Hermes DM, et al. Evaluation of heteroresistance to polymyxin B among carbapenem-susceptible and -resistant Pseudomonas aeruginosa. J Med Microbiol. 2013;62:1184–9.
Bardet L, et al. Deciphering Heteroresistance to Colistin in a Klebsiella pneumoniae Isolate from Marseille, France. Antimicrob Agents Chemother. 2017;61:e00356–17.
Morales-León F, Lima CA, González-Rocha G, Opazo-Capurro A, Bello-Toledo H. Colistin Heteroresistance among Extended Spectrum β-lactamases-Producing Klebsiella pneumoniae. Microorganisms 2020;8:E1279.
Cheong HS, Kim SY, Wi YM, Peck KR, Ko KS. Colistin Heteroresistance in Klebsiella Pneumoniae Isolates and Diverse Mutations of PmrAB and PhoPQ in Resistant Subpopulations. J Clin Med. 2019;8:1444.
Li J, et al. Emergence of polymyxin B-heteroresistant hypervirulent Klebsiella pneumoniae from an individual in the community with asymptomatic bacteriuria. BMC Microbiol. 2022;22:47.
Band VI, et al. Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection. mBio. 2018;9:e02448–17.
Liao W, et al. Resistance and Heteroresistance to Colistin in Escherichia coli Isolates from Wenzhou, China. Infect Drug Resist. 2020;13:3551–61.
Band VI, et al. Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae. Nat Microbiol. 2016;1:16053.
Winfield MD, Groisman EA. Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes. PNAS. 2004;101:17162–7.
Guckes KR, et al. Signaling by two-component system noncognate partners promotes intrinsic tolerance to polymyxin B in uropathogenic Escherichia coli. Sci Signal. 2017;10:eaag1775.
Yang B, et al. Identification of novel PhoP-PhoQ regulated genes that contribute to polymyxin B tolerance in Pseudomonas aeruginosa. Microorganisms. 2021;9:344.
Ryan RP, et al. Interspecies signalling via the Stenotrophomonas maltophilia diffusible signal factor influences biofilm formation and polymyxin tolerance in Pseudomonas aeruginosa. Mol Microbiol. 2008;68:75–86.
Cui P, et al. Disruption of membrane by colistin kills uropathogenic Escherichia coli persisters and enhances killing of other antibiotics. Antimicrob Agents Chemother. 2016;60:6867–71.
Baek MS, Chung ES, Jung DS, Ko KS. Effect of colistin-based antibiotic combinations on the eradication of persister cells in Pseudomonas aeruginosa. J Antimicrob Chemother. 2020;75:917–24.
Kashyap S, Kaur S, Sharma P, Capalash N. Combination of colistin and tobramycin inhibits persistence of Acinetobacter baumannii by membrane hyperpolarization and down-regulation of efflux pumps. Microbes Infect. 2021;23:104795.
Niu H, et al. Identification of Anti-Persister Activity against Uropathogenic Escherichia coli from a Clinical Drug Library. Antibiotics. 2015;4:179–87.
Brown P, Dawson MJ. Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections. J Antibiot. 2017;70:386–94.
Eckburg PB, et al. Safety, tolerability, pharmacokinetics, and drug interaction potential of SPR741, an intravenous potentiator, after single and multiple ascending doses and when combined with β-Lactam antibiotics in healthy subjects. Antimicrob Agents Chemother. 2019;63:e00892–19.
Butler MS, Paterson DL. Antibiotics in the clinical pipeline in October 2019. J Antibiot. 2020;73:329–64.
Spero Therapeutics. Study to Assess the Intrapulmonary Pharmacokinetics of SPR206 in Healthy Volunteers. Clinical Trial Identifier NCT04868292. 2021. https://www.bolderscience.com/trial/nct04868292/.
Spero Therapeutics. 2021. Phase 1 Study of PK and Safety of SPR206 in Subjects With Various Degrees Of Renal Function. Clinical Trial Identifier NCT04865393.
Spero Therapeutics. A First in Human Study of the Safety and Tolerability of Single and Multiple Doses of SPR206 in Healthy Volunteers. Clinical Trial Identifier NCT03792308. 2018. https://www.bolderscience.com/trial/nct03792308/
Ash C, Priest FG, Collins MD. Molecular identification of rRNA group 3 bacilli (Ash, Farrow, Wallbanks and Collins) using a PCR probe test: proposal for the creation of a new genus Paenibacillus. Antonie van Leeuwenhoek. 1993;64:253–60.
Jones TSG. The chemical nature of aerosporin. Biochem J. 1948;42:xxxv.
Jones TSG. The chemical basis for the classification of the polymyxins. Biochem J. 1948;43:xxvi.
Jones TSG. Chemical evidence for the multiplicity of antibiotics produced by Bacillus polymyxa. Ann N. Y Acad Sci. 1949;51:909–16.
Brownlee G, Jones TSG. The polymyxins; a related series of antibiotics derived from B. polymyxa. Biochem J. 1948;43:xxv.
Shepherd RG, et al. Chemical studies on polymyxin; isolation and preliminary purification. J Am Chem Soc. 1948;70:3771–4.
White HJ, Alverson CM, Baker MJ, Jackson ER. Comparative biological studies of Polymyxin and “Aerosporin. Ann N. Y Acad Sci. 1949;51:879–90.
Brownlee G, Bushby SRM, Short EI. Comparative biological studies of Polymyxin A and Polymyxin D. Ann N. Y Acad Sci. 1949;51:891–6.
Bell PH, et al. Chemical studies on polymyxin: comparison with “Aerosporin. Ann N. Y Acad Sci. 1949;51:897–908.
Stansly PG, Brownlee G. Nomenclature of polymyxin antibiotics. Nature. 1949;163:611–611.
Brownlee G. Antibiotics derived from Bacillus Polymyxa. Ann N. Y Acad Sci. 1949;51:875–8.
Koyama Y, Kurosasa A, Tsuchiya A, Takakuta K. A new antibiotic ‘colistin’ produced by spore-forming soil bacteria. J Antibiot. 1950;3:457–8.
Wilkinson S. Identity of colistin and polymyxin E. Lancet. 1963;281:922–3.
Suzuki T, Hayashi K, Fujikawa K, Tsukamoto K. The chemical structure of polymyxin E: the identities of polymyxin E1 with colistin A and of polymyxin E2 with colistin B∗. J Biochem. 1965;57:226–7.
Langendries S, Goormachtig S. Paenibacillus polymyxa, a jack of all trades. Environ Microbiol. 2021;23:5659–69.
Stansly PG. The polymyxins: a review and assessment. Am J Med. 1949;7:807–18.
Clifford HE, Stewart GT. Intraventricular administration of a new derivative of polymyxin B in menningitis due to P. Pyogyanea. Lancet. 1961;278:177–80.
Ross S, Puig JR, Zaremba EA. Colistin: some preliminary laboratory and clinical observations in specific gastroenteritis in infants and children. Antibiot Annu. 1959;7:89–100.
Nation RL, et al. Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus. Lancet Infect Dis. 2015;15:225–34.
Falagas ME, Kasiakou SK, Saravolatz LD. Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin Infect Dis. 2005;40:1333–41.
Brown JM, Dorman DC, Roy LP. Acute renal failure due to overdosage of colistin. Med J Aust. 1970;2:923–4.
Koch-Weser J. Adverse effects of sodium colistimethate: manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med. 1970;72:857.
Ryan KJ. Colistimethate toxicity. Report of a fatal case in a previously healthy child. JAMA. 1969;207:2099–101.
Duncan DA. Colistin toxicity. Neuromuscular and renal manifestations. Two cases treated by hemodialysis. Minn Med. 1973;56:31–5.
Wolinsky E, Hines JD. Neurotoxic and nephrotoxic effects of colistin in patients with renal disease. N. Engl J Med. 1962;266:759–62.
Price DJE, Graham DI. Effects of large doses of colistin sulphomethate sodium on renal function. BMJ. 1970;4:525–7.
Lindesmith LA. Reversible respiratory paralysis associated with polymyxin therapy. Ann Intern Med. 1968;68:318.
Nation RL, Li J. Colistin in the 21st century. Curr Opin Infect. 2009;22:535–43.
Conway SP, et al. Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis. Thorax 1997;52:987–93.
Ledson MJ, Gallagher MJ, Cowperthwaite C, Convery RP, Walshaw MJ. Four years’ experience of intravenous colomycin in an adult cystic fibrosis unit. Eur Respir J. 1998;12:592–4.
Cunningham S. Short report: Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child. 2001;84:432–3.
Jensen T, et al. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother. 1987;19:831–8.
Wertheim H, et al. Global survey of polymyxin use: a call for international guidelines. J Glob Antimicrob Resist. 2013;1:131–4.
Tsuji BT, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39:10–39.
Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10:R27.
Vaara M, et al. A novel polymyxin derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane. Antimicrob Agents Chemother. 2010;54:3341–6.
Vaara M, et al. Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents. Antimicrob Agents Chemother. 2008;52:3229–36.
Brown P, et al. Design of next generation polymyxins with lower toxicity: the discovery of SPR206. ACS Infect Dis. 2019;5:1645–56.
Stokniene J, et al. Bi-functional alginate oligosaccharide–polymyxin conjugates for improved treatment of multidrug-resistant Gram-negative bacterial infections. Pharmaceutics. 2020;12:1080.
Gallardo-Godoy A, et al. Structure-function studies of polymyxin B lipononapeptides. Molecules 2019;24:553.
Velkov T, Roberts KD Discovery of novel polymyxin-like antibiotics In: Li J, Nation RL, Kaye KS, editors. Polymyxin Antibiotics: From Laboratory Bench to Bedside, Vol 1145. Cham, Switzerland: Springer International Publishing; 2019. p. 343–62.
Velkov T, et al. Teaching ‘old’ polymyxins new tricks: new-generation lipopeptides targeting Gram-negative ‘superbugs. ACS Chem Biol. 2014;9:1172–7.
Zhao J, et al. Transcriptomic analysis of the activity of a novel polymyxin against Staphylococcus aureus. mSphere. 2016;1:e00119–16.
Trimble MJ, Mlynárčik P, Kolář M, Hancock REW. Polymyxin: alternative mechanisms of action and resistance. Cold Spring Harb Perspect Med. 2016;6:a025288.
Vaara M. Polymyxins and their potential next generation as therapeutic antibiotics. Front Microbiol. 2019;10:1689.
Yu Z, Qin W, Lin J, Fang S, Qiu J. Antibacterial mechanisms of polymyxin and bacterial resistance. Biomed Res Int. 2015;2015:1–11.
Rabanal F, Cajal Y. Recent advances and perspectives in the design and development of polymyxins. Nat Prod Rep. 2017;34:886–908.
Pristovšek P, Kidrič J. Solution structure of polymyxins B and E and effect of binding to lipopolysaccharide: an NMR and molecular modeling study. J Med Chem. 1999;42:4604–13.
Yuan Y, et al. Control of the polymyxin analog ratio by domain swapping in the nonribosomal peptide synthetase of Paenibacillus polymyxa. J Ind Microbiol Biotechnol. 2020;47:551–62.
Felnagle EA, et al. Nonribosomal Peptide Synthetases Involved in the Production of Medically Relevant Natural Products. Mol Pharmaceutics. 2008;5:191–211.
Thibaut D, et al. Purification of peptide synthetases involved in pristinamycin I biosynthesis. J Bacteriol. 1997;179:697–704.
Choi S-K, et al. Identification of a polymyxin synthetase gene cluster of Paenibacillus polymyxa and heterologous expression of the gene in Bacillus subtilis. J Bacteriol. 2009;191:3350–8.
Miller BR, Gulick AM. Structural biology of non-ribosomal peptide synthetases. Methods Mol Biol. 2016;1401:3–29.
Izoré T, et al. Structures of a non-ribosomal peptide synthetase condensation domain suggest the basis of substrate selectivity. Nat Commun. 2021;12:2511.
Galea CA, et al. Functional Characterization of the Unique Terminal Thioesterase Domain from Polymyxin Synthetase. Biochemistry 2017;56:657–68.
Zhong L, et al. Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis. Nat Commun. 2021;12:296.
Tambadou F, et al. Characterization of the colistin (polymyxin E1 and E2) biosynthetic gene cluster. Arch Microbiol. 2015;197:521–32.
Galea CA, et al. Characterization of the polymyxin D synthetase biosynthetic cluster and product profile of Paenibacillus polymyxa ATCC 10401. J Nat Prod. 2017;80:1264–74.
Shaheen M, Li J, Ross AC, Vederas JC, Jensen SE. Paenibacillus polymyxa PKB1 Produces Variants of Polymyxin B-Type Antibiotics. Chem Biol. 2011;18:1640–8.
Niu B, et al. Polymyxin P is the active principle in suppressing phytopathogenic Erwinia spp. by the biocontrol rhizobacterium Paenibacillus polymyxa M-1. BMC Microbiol. 2013;13:137.
Martin NI, et al. Isolation, structural characterization, and properties of mattacin (polymyxin M), a cyclic peptide antibiotic produced by Paenibacillus kobensis M. J Biol Chem. 2003;278:13124–32.
Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited. Clin Microbiol Rev. 2008;21:449–65.
Poirel L, Jayol A, Nordmann P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev. 2017;30:557–96.
Schindler M, Osborn MJ. Interaction of divalent cations and polymyxin B with lipopolysaccharide. Biochemistry 1979;18:4425–30.
Hancock REW, et al. Cationic peptides: a class of antibiotics able to access the self-promoted uptake pathway across the Pseudomonas aeruginosa outer membrane. In: Molecular Biology of Pseudomonads. Washington, DC: ASM Press; 1996. p. 441–50.
Sabnis A, et al. Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane. eLife. 2021;10:e65836.
Okuda S, Sherman DJ, Silhavy TJ, Ruiz N, Kahne D. Lipopolysaccharide transport and assembly at the outer membrane: the PEZ model. Nat Rev Microbiol. 2016;14:337–45.
Sperandeo P, et al. Functional Analysis of the Protein Machinery Required for Transport of Lipopolysaccharide to the Outer Membrane of Escherichia coli. J Bacteriol. 2008;190:4460–9.
Werneburg M, et al. Inhibition of Lipopolysaccharide Transport to the Outer Membrane in Pseudomonas aeruginosa by Peptidomimetic Antibiotics. ChemBioChem. 2012;13:1767–75.
Mogi T, et al. Polymyxin B identified as an inhibitor of alternative NADH Dehydrogenase and Malate: Quinone Oxidoreductase from the Gram-positive bacterium Mycobacterium smegmatis. J Biochem. 2009;146:491–9.
Pamp SJ, Gjermansen M, Johansen HK, Tolker-Nielsen T. Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes. Mol Microbiol. 2008;68:223–40.
McCall IC, Shah N, Govindan A, Baquero F, Levin BR. Antibiotic Killing of Diversely Generated Populations of Nonreplicating Bacteria. Antimicrob Agents Chemother. 2019;63:13.
Yin J, et al. Mechanisms of bactericidal action and resistance of polymyxins for Gram-positive bacteria. Appl Microbiol Biotechnol. 2020;104:3771–80.
Rudilla H, et al. Novel synthetic polymyxins kill Gram-positive bacteria. J Antimicrob Chemother. 2018;73:3385–90.
Velkov T, Thompson PE, Nation RL, Li J. Structure−activity relationships of polymyxin antibiotics. J Med Chem. 2010;53:1898–916.
de Visser PC, et al. Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach: synthesis of polymyxin B1 and analogues. Pept Res. 2003;61:298–306.
Gallardo-Godoy A, et al. Activity and predicted nephrotoxicity of synthetic antibiotics based on polymyxin B. J Med Chem. 2016;59:1068–77.
Lu S, Walters G, Parg R, Dutcher JR. Nanomechanical response of bacterial cells to cationic antimicrobial peptides. Soft Matter. 2014;10:1806–15.
Ofek I, et al. Antibacterial synergism of polymyxin B nonapeptide and hydrophobic antibiotics in experimental gram-negative infections in mice. Antimicrob Agents Chemother. 1994;38:374–7.
Viljanen P, Vaara M. Susceptibility of gram-negative bacteria to polymyxin B nonapeptide. Antimicrob Agents Chemother. 1984;25:701–5.
Bhattacharjya S, David SA, Mathan VI, Balaram P. Polymyxin B nonapeptide: Conformations in water and in the lipopolysaccharide-bound state determined by two-dimensional NMR and molecular dynamics. Biopolymers. 1997;41:251–65.
Nang SC, Li J, Velkov T. The rise and spread of mcr plasmid-mediated polymyxin resistance. Crit Rev Microbiol. 2019;45:131–61.
Huttner B, et al. Drugs of Last Resort? The Use of Polymyxins and Tigecycline at US Veterans Affairs Medical Centers, 2005-2010. PLOS ONE. 2012;7:e36649.
Olaitan AO, Morand S, Rolain J-M. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol. 2014;5:643.
Balaban NQ, et al. Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol. 2019;17:441–8.
El-Halfawy OM, Valvano MA. Antimicrobial heteroresistance: an emerging field in need of clarity. Clin Microbiol Rev. 2015;28:191–207.
Moffatt JH, et al. Colistin resistance in Acinetobacter baumannii Is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother. 2010;54:4971–7.
Raetz CRH, Reynolds CM, Trent MS, Bishop RE. Lipid A modification systems in Gram-negative bacteria. Annu Rev Biochem. 2007;76:295–329.
Berglund B. Acquired resistance to colistin via chromosomal and plasmid-mediated mechanisms in Klebsiella pneumoniae. Infect Microbes Dis. 2019;1:10–19.
Jayol A, et al. Resistance to colistin associated with a single amino acid change in protein PmrB among Klebsiella pneumoniae isolates of worldwide origin. Antimicrob Agents Chemother. 2014;58:4762–6.
Liu Y-Y, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16:161–8.
Olaitan AO, et al. Worldwide emergence of colistin resistance in Klebsiella pneumoniae from healthy humans and patients in Lao PDR, Thailand, Israel, Nigeria and France owing to inactivation of the PhoP/PhoQ regulator mgrB: an epidemiological and molecular study. Int J Antimicrob Agents. 2014;44:500–7.
Cannatelli A, Santos-Lopez A, Giani T, Gonzalez-Zorn B, Rossolini GM. Polymyxin Resistance Caused by mgrB Inactivation Is Not Associated with Significant Biological Cost in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015;59:2898–2900.
Aires CAM, Pereira PS, Asensi MD, Carvalho-Assef APD. mgrB Mutations Mediating Polymyxin B Resistance in Klebsiella pneumoniae Isolates from Rectal Surveillance Swabs in Brazil. Antimicrob Agents Chemother. 2016;60:6969–72.
Lesho E, et al. Emergence of Colistin-Resistance in Extremely Drug-Resistant Acinetobacter baumannii Containing a Novel pmrCAB Operon During Colistin Therapy of Wound Infections. J Infect Dis. 2013;208:1142–51.
Wösten MMSM, Kox LFF, Chamnongpol S, Soncini FC, Groisman EA. A Signal Transduction System that Responds to Extracellular Iron. Cell. 2000;103:113–25.
Kox LFF, Wösten MMSM, Groisman EA. A small protein that mediates the activation of a two-component system by another two-component system. EMBO J. 2000;19:1861–72.
Véscovi EG, Soncini FC, Groisman EA. Mg2+ as an Extracellular Signal: Environmental Regulation of Salmonella Virulence. Cell 1996;84:165–74.
Phan M-D, et al. Modifications in the pmrB gene are the primary mechanism for the development of chromosomally encoded resistance to polymyxins in uropathogenic Escherichia coli. J Antimicrob Chemother. 2017;72:2729–36.
Lippa AM, Goulian M. Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide. PLOS Genet. 2009;5:e1000788.
Simpson BW, Trent MS. Pushing the envelope: LPS modifications and their consequences. Nat Rev Microbiol. 2019;17:403–16.
Wang R, et al. The global distribution and spread of the mobilized colistin resistance gene mcr-1. Nat Commun. 2018;9:1179.
Snesrud E, et al. A Model for Transposition of the Colistin Resistance Gene mcr-1 by ISApl1. Antimicrob Agents Chemother. 2016;60:6973–6.
Carroll LM, et al. Identification of novel mobilized colistin resistance gene mcr-9 in a multidrug-resistant, colistin-susceptible Salmonella enterica serotype typhimurium isolate. mBio. 2019;10:e00853–19.
Skov RL, Monnet DL. Plasmid-mediated colistin resistance (mcr-1 gene): three months later, the story unfolds. Eur Surveill. 2016;21:30155.
Wang C, et al. Identification of novel mobile colistin resistance gene mcr-10. Emerg Microbes Infect. 2020;9:508–16.
Xavier BB, et al. Identification of a novel plasmid-mediated colistin-resistance gene, mcr-2, in Escherichia coli, Belgium, June 2016. Eur Surveill. 2016;21:30280.
Yin W, et al. Novel Plasmid-Mediated Colistin Resistance Gene mcr-3 in Escherichia coli. mBio. 2017;8:e00543–17.
Carattoli A, et al. Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016. Eur Surveill. 2017;22:30589.
Borowiak M, et al. Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B. J Antimicrob Chemother. 2017;72:3317–24.
AbuOun M, et al. mcr-1 and mcr-2 (mcr-6.1) variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015. J Antimicrob Chemother. 2017;72:2745–9.
Yang Y-Q, Li Y-X, Lei C-W, Zhang A-Y, Wang H-N. Novel plasmid-mediated colistin resistance gene mcr-7.1 in Klebsiella pneumoniae. J Antimicrob Chemother. 2018;73:1791–5.
Wang X, et al. Emergence of a novel mobile colistin resistance gene, mcr-8, in NDM-producing Klebsiella pneumoniae. Emerg Micro Infect. 2018;7:1–9.
Zhao Q, et al. Clinical Impact of Colistin Banning in Food Animal on mcr-1-Positive Enterobacteriaceae in Patients From Beijing, China, 2009-2019: A Long-Term Longitudinal Observational Study. Front Microbiol. 2022;13:826624.
Majewski P, et al. Plasmid Mediated mcr-1.1 Colistin-Resistance in Clinical Extraintestinal Escherichia coli Strains Isolated in Poland. Front Microbiol. 2021;12:547020.
Farzana R, et al. Emergence of Mobile Colistin Resistance (mcr-8) in a Highly Successful Klebsiella pneumoniae Sequence Type 15 Clone from Clinical Infections in Bangladesh. mSphere. 2020;5:e00023–20.
Yang Q, et al. Balancing mcr-1 expression and bacterial survival is a delicate equilibrium between essential cellular defence mechanisms. Nat Commun. 2017;8:2054.
Feng S, et al. MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria. Emerg Microbes Infect. 2022;11:1236–49.
MacNair CR, et al. Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics. Nat Commun. 2018;9:458.
Brennan-Krohn T, Pironti A, Kirby JE. Synergistic activity of colistin-containing combinations against colistin-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2018;62:e00873–18.
Tzeng Y-L, et al. Cationic antimicrobial peptide resistance in Neisseria meningitidis. J Bacteriol. 2005;187:5387–96.
Yin J, et al. Inactivation of polymyxin by hydrolytic mechanism. Antimicrob Agents Chemother. 2016;63:e02378–18.
Ito-Kagawa M, Koyama Y. Selective cleavage of a peptide antibiotic, colistin by colistinase. J Antibiot. 1980;33:1551–5.
Hamel M, Rolain J-M, Baron SA. The history of colistin resistance mechanisms in bacteria: progress and challenges. Microorganisms. 2021;9:442.
Sherman EX, Wozniak JE, Weiss DS Methods to Evaluate Colistin Heteroresistance in Acinetobacter baumannii In: Biswas I, Rather PN, editors. Acinetobacter baumannii: Methods and Protocols. Vol 1946. New York, NY: Springer; 2019. p. 39–50.
Mashaly GE-S, Mashaly ME-S. Colistin-heteroresistance in carbapenemase-producing Enterobacter species causing hospital-acquired infections among Egyptian patients. J Glob Antimicrob Resist. 2021;24:108–13.
Band VI, et al. Colistin Heteroresistance Is Largely Undetected among Carbapenem-Resistant Enterobacterales in the United States. mBio. 2021;12:e02881–20.
Hjort K, Nicoloff H, Andersson DI. Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica. Mol Microbiol. 2016;102:274–89.
Nicoloff H, Hjort K, Levin BR, Andersson DI. The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification. Nat Microbiol. 2019;4:504–14.
Thaipisuttikul I, et al. A divergent Pseudomonas aeruginosa palmitoyltransferase essential for cystic fibrosis-specific lipid A. Mol Microbiol. 2014;91:158–74.
Pompilio A, et al. Cooperative pathogenicity in cystic fibrosis: Stenotrophomonas maltophilia modulates Pseudomonas aeruginosa virulence in mixed biofilm. Front Microbiol. 2015;6:951.
Zusman O, et al. Systematic review and meta-analysis of in vitro synergy of polymyxins and carbapenems. Antimicrob Agents Chemother. 2013;57:5104–11.
Berditsch M, et al. Synergistic effect of membrane-active peptides polymyxin B and gramicidin S on multidrug-resistant strains and biofilms of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59:5288–96.
Aye SM, et al. Polymyxin triple combinations against polymyxin-resistant, multidrug-resistant, KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2020;64:e00246–20.
Ma X, et al. Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella pneumoniae and Hinders Emergence of Resistant Subpopulation in vitro. Front Microbiol. 2019;10:2029.
Tian Y, Zhang Q, Wen L, Chen J. Combined effect of Polymyxin B and Tigecycline to overcome Heteroresistance in Carbapenem-Resistant Klebsiella pneumoniae. Microbiol Spectr. 2021;9:e00152–21.
Band VI, et al. Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection. Nat Microbiol. 2019;4:1627–35.
Duwe AK, Rupar CA, Horsman GB, Vas SI. In vitro cytotoxicity and antibiotic activity of polymyxin B nonapeptide. Antimicrob Agents Chemother. 1986;30:340–1.
Zabawa TP, Pucci MJ, Parr TR, Lister T. Treatment of Gram-negative bacterial infections by potentiation of antibiotics. Curr Opin Microbiol. 2016;33:7–12.
Nang SC, Azad MAK, Velkov T, Zhou QTony, Li J. Rescuing the last-line polymyxins: achievements and challenges. Pharm Rev. 2021;73:679–728.
Zurawski DV, et al. SPR741, an antibiotic adjuvant, potentiates the in vitro and in vivo activity of rifampin against clinically relevant extensively drug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2017;61:e01239–17.
Zavascki AP, Nation RL. Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B? Antimicrob Agents Chemother. 2017;61:e02319–16.
Bruss J, et al. Single- and multiple-ascending-dose study of the safety, tolerability, and pharmacokinetics of the polymyxin derivative SPR206. Antimicrob Agents Chemother. 2021;65:e0073921.
Vaara M, Vaara T. Sensitization of Gram-negative bacteria to antibiotics and complement by a nontoxic oligopeptide. Nature 1983;303:526–8.
Nikaido H. Molecular Basis of Bacterial Outer Membrane Permeability Revisited. Microbiol Mol Biol Rev. 2003;67:593–656.
Kim S, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2021;49:D1388–D1395.
This work was supported by the 250th Anniversary Fund for Innovation in Undergraduate Education, the Program for Community Engaged Scholarship, and the Council on Science and Technology at Princeton University (MPB). The content is solely the responsibility of the authors and does not necessarily represent the views of the funding agencies.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Chiu, S., Hancock, A.M., Schofner, B.W. et al. Causes of polymyxin treatment failure and new derivatives to fill the gap. J Antibiot (2022). https://doi.org/10.1038/s41429-022-00561-3