Currently, polymyxin (polymyxin B and colistin) is the last antibiotic used to treat multidrug resistant Klebsiella pneumoniae, especially after carbapenem-resistant Klebsiella pneumoniae (CRKP) emerged. Nevertheless, with reports of polymyxin resistance in clinical isolates increased gradually, it posed a great challenge to clinical treatment. Klebsiella pneumoniae plays an important role in the process of polymyxin resistance in Klebsiella pneumoniae, mediating polymyxin resistance by modifying lipopolysaccharide (LPS), mgrB negative feedback regulators, and efflux pumps through two-component regulatory systems (TCSs). This article provides a theoretical basis for the study of polymyxin and the discovery of potential drugs for clinical relevant Klebsiella pneumoniae infection by reviewing the basis of signal transduction, activation conditions, and feedback pathways through which overexpression of TCSs leads to changes in the minimum inhibitory cocentration (MIC) value of Klebsiella pneumoniae, and elaborating the mechanism of TCSs leading to resistance of Klebsiella pneumoniae to polymyxin.

1.Navon-Venezia S, Kondratyeva K, Carattoli A. Klebsiella pneumoniae: a major worldwide source and shuttle for antibiotic resistance[J]. FEMS Microbiol Rev, 2017, 41(3): 252-275. DOI: 10.1093/femsre/fux013.

2.Aghapour Z, Gholizadeh P, Ganbarov K, et al. Molecular mechanisms related to colistin resistance in Enterobacteriaceae[J]. Infect Drug Resist, 2019, 12: 965-975. DOI: 10.2147/IDR.S199844.

3.Kallel H, Bahloul M, Hergafi L, et al. Colistin as a salvage therapy for nosocomial infections caused by multidrug-resistant bacteria in the ICU[J]. Int J Antimicrob Agents, 2006, 28(4): 366-369. DOI: 10.1016/j.ijantimicag.2006.07.008.

4.CHINET中国细菌耐药监测网. CHINET 2022年上半年细菌耐药监测结果[J/OL]. (2022-09-13) [2023-01-04]. [China Antimicrobial Surveillance Network. CHINET monitoring results of drug-resistant bateria[J/OL]. (2022-09-13) [2023-01-04].] http://www.chinets.com/Document/Index?pageIndex=0#.

5.Tierney AR, Rather PN. Roles of two-component regulatory systems in antibiotic resistance[J]. Future Microbiol, 2019, 14(6): 533-552. DOI: 10.2217/fmb-2019-0002.

6.Moffatt JH, Harper M, Harrison P, et al. Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production[J]. Antimicrob Agents Chemother, 2010, 54(12): 4971-4977. DOI: 10.1128/AAC.00834-10.

7.Jayol A, Nordmann P, Brink A, et al. Heteroresistance to colistin in Klebsiella pneumoniae associated with alterations in the PhoPQ regulatory system[J]. Antimicrob Agents Chemother, 2015, 59(5): 2780-2784. DOI: 10.1128/AAC.05055-14.

8.Olaitan AO, Morand S, Rolain JM. Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria[J]. Front Microbiol, 2014, 5: 643. DOI: 10.3389/fmicb.2014.00643.

9.Kim SY, Choi HJ, Ko KS. Differential expression of two-component systems, pmrAB and phoPQ, with different growth phases of Klebsiella pneumoniae in the presence or absence of colistin[J]. Curr Microbiol, 2014, 69(1): 37-41. DOI: 10.1007/s00284-014-0549-0.

10.Naha S, Sands K, Mukherjee S, et al. A 12 year experience of colistin resistance in Klebsiella pneumoniae causing neonatal sepsis: two-component systems, efflux pumps, lipopolysaccharide modification and comparative phylogenomics[J]. J Antimicrob Chemother, 2022, 77(6): 1586-1591. DOI: 10.1093/jac/dkac083.

11.Gunn JS, Miller SI. PhoP-PhoQ activates transcription of pmrAB, encoding a two-component regulatory system involved in Salmonella typhimurium antimicrobial peptide resistance[J]. J Bacteriol, 1996, 178(23): 6857-6864. DOI: 10.1128/jb.178.23.6857-6864.1996.

12.Trent MS, Ribeiro AA, Lin S, et al. An inner membrane enzyme in Salmonella and Escherichia coli that transfers 4-amino-4-deoxy-L-arabinose to lipid A: induction on polymyxin-resistant mutants and role of a novel lipid-linked donor[J]. J Biol Chem, 2001, 276(46): 43122-43131. DOI: 10.1074/jbc.M106961200.

13.Dalebroux ZD, Miller SI. Salmonellae PhoPQ regulation of the outer membrane to resist innate immunity[J]. Curr Opin Microbiol, 2014, 17: 106-113. DOI: 10.1016/j.mib.2013.12.005.

14.Bearson BL, Wilson L, Foster JW. A low pH-inducible, PhoPQ-dependent acid tolerance response protects Salmonella typhimurium against inorganic acid stress[J]. J Bacteriol, 1998, 180(9): 2409-2417. DOI: 10.1128/JB.180.9.2409-2417.1998.

15.Bader MW, Navarre WW, Shiau W, et al. Regulation of Salmonella typhimurium virulence gene expression by cationic antimicrobial peptides[J]. Mol Microbiol, 2003, 50(1): 219-230. DOI: 10.1046/j.1365-2958.2003.03675.x.

16.García Véscovi E, Soncini FC, Groisman EA. Mg2+ as an extracellular signal: environmental regulation of Salmonella virulence[J]. Cell, 1996, 84(1): 165-174. DOI: 10.1016/s0092-8674(00)81003-x.

17.Viarengo G, Sciara MI, Salazar MO, et al. Unsaturated long chain free fatty acids are input signals of the Salmonella enterica PhoP/PhoQ regulatory system[J]. J Biol Chem, 2013, 288(31): 22346-22358. DOI: 10.1074/jbc.M113.472829.

18.Kox LF, Wosten MM, Groisman EA. A small protein that mediates the activation of a two-component system by another two-component system[J]. EMBO J, 2000, 19(8): 1861-1872. DOI: 10.1093/emboj/19.8.1861.

19.Kato A, Latifi T, Groisman EA. Closing the loop: the PmrA/PmrB two-component system negatively controls expression of its posttranscriptional activator PmrD[J]. Proc Natl Acad Sci USA, 2003, 100(8): 4706-4711. DOI: 10.1073/pnas.0836837100.

20.Winfield MD, Groisman EA. Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes[J]. Proc Natl Acad Sci USA, 2004, 101(49): 17162-17167. DOI: 10.1073/pnas.0406038101.

21.Wösten MM, Groisman EA. Molecular characterization of the PmrA regulon[J]. J Biol Chem, 1999, 274(38): 27185-27190. DOI: 10.1074/jbc.274.38.27185.

22.Morales-León F, Lima CA, González-Rocha G, et al. Colistin heteroresistance among extended spectrum β-lactamases-producing Klebsiella pneumoniae[J]. Microorganisms, 2020, 8(9): 1279. DOI: 10.3390/microorganisms8091279.

23.Uz Zaman T, Albladi M, Siddique MI, et al. Insertion element mediated mgrB disruption and presence of ISKpn28 in colistin-resistant Klebsiella pneumoniae isolates from Saudi Arabia[J]. Infect Drug Resist, 2018, 11: 1183-1187. DOI: 10.2147/IDR.S161146.

24.Olaitan AO, Diene SM, Kempf M, 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[J]. Int J Antimicrob Agents, 2014, 44(6): 500-507. DOI: 10.1016/j.ijantimicag.2014.07.020.

25.Főldes A, Oprea M, Székely E, et al. Characterization of carbapenemase-producing Klebsiella pneumoniae isolates from two romanian hospitals co-presenting resistance and heteroresistance to colistin[J]. Antibiotics (Basel), 2022, 11(9): 1171. DOI: 10.3390/antibiotics11091171.

26.Halaby T, Kucukkose E, Janssen AB, et al. Genomic characterization of colistin heteroresistance in Klebsiella pneumoniae during a nosocomial outbreak[J]. Antimicrob Agents Chemother, 2016, 60(11): 6837-6843. DOI: 10.1128/AAC.01344-16.

27.Aires CA, Pereira PS, Asensi MD, et al. mgrB mutations mediating polymyxin B resistance in Klebsiella pneumoniae isolates from rectal surveillance swabs in Brazil[J]. Antimicrob Agents Chemother, 2016, 60(11): 6969-6972. DOI: 10.1128/AAC.01456-16.

28.Band VI, Satola SW, Burd EM, et al. Carbapenem-resistant Klebsiella pneumoniae exhibiting clinically undetected colistin heteroresistance leads to treatment failure in a murine model of infection[J]. mBio, 2018, 9(2): e02448-17. DOI: 10.1128/mBio.02448-17.

29.Bardet L, Baron S, Leangapichart T, et al. Deciphering heteroresistance to colistin in a Klebsiella pneumoniae isolate from Marseille, France[J]. Antimicrob Agents Chemother, 2017, 61(6): e00356-17. DOI: 10.1128/AAC.00356-17.

30.Cheng HY, Chen YF, Peng HL. Molecular characterization of the PhoPQ-PmrD-PmrAB mediated pathway regulating polymyxin B resistance in Klebsiella pneumoniae CG43[J]. J Biomed Sci, 2010, 17(1): 60. DOI: 10.1186/1423-0127-17-60.

31.Mitrophanov AY, Jewett MW, Hadley TJ, et al. Evolution and dynamics of regulatory architectures controlling polymyxin B resistance in enteric bacteria[J]. PLoS Genet, 2008, 4(10): e1000233. DOI: 10.1371/journal.pgen.1000233.

32.Nirwan PK, Chatterjee N, Panwar R, et al. Mutations in two component system (PhoPQ and PmrAB) in colistin resistant Klebsiella pneumoniae from North Indian tertiary care hospital[J]. J Antibiot (Tokyo), 2021, 74(7): 450-457. DOI: 10.1038/s41429-021-00417-2.

33.Cannatelli A, Giani T, D'andrea MM, et al. MgrB inactivation is a common mechanism of colistin resistance in KPC-producing Klebsiella pneumoniae of clinical origin[J]. Antimicrob Agents Chemother, 2014, 58(10): 5696-5703. DOI: 10.1128/AAC.03110-14.

34.Poirel L, Jayol A, Bontron S, et al. The mgrB gene as a key target for acquired resistance to colistin in Klebsiella pneumoniae[J]. J Antimicrob Chemother, 2015, 70(1): 75-80. DOI: 10.1093/jac/dku323.

35.Liu X, Wu Y, Zhu Y, et al. Emergence of colistin-resistant hypervirulent Klebsiella pneumoniae (CoR-HvKp) in China[J]. Emerg Microbes Infect, 2022, 11(1): 648-661. DOI: 10.1080/22221751.2022.2036078.

36.Kidd TJ, Mills G, Sá-Pessoa J, et al. A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence[J]. EMBO Mol Med, 2017, 9(4): 430-447. DOI: 10.15252/emmm.201607336.

37.Seo J, Wi YM, Kim JM, et al. Detection of colistin-resistant populations prior to antibiotic exposure in KPC-2-producing Klebsiella pneumoniae clinical isolates[J]. J Microbiol, 2021, 59(6): 590-597. DOI: 10.1007/s12275-021-0610-1.

38.Cheong HS, Kim SY, Wi YM, et al. Colistin heteroresistance in Klebsiella Pneumoniae isolates and diverse mutations of PmrAB and PhoPQ in resistant subpopulations[J]. J Clin Med, 2019, 8(9): 1444. DOI: 10.3390/jcm8091444.

39.Falagas ME, Rafailidis PI, Matthaiou DK. Resistance to polymyxins: mechanisms, frequency and treatment options[J]. Drug Resist Updat, 2010, 13(4-5): 132-138. DOI: 10.1016/j.drup.2010.05.002.

40.Gunn JS. The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more[J]. Trends Microbiol, 2008, 16(6): 284-290. DOI: 10.1016/j.tim.2008.03.007.

41.Jayol A, Poirel L, Brink A, et al. Resistance to colistin associated with a single amino acid change in protein PmrB among Klebsiella pneumoniae isolates of worldwide origin[J]. Antimicrob Agents Chemother, 2014, 58(8): 4762-4766. DOI: 10.1128/AAC.00084-14.

42.Wand ME, Bock LJ, Sutton JM. Retention of virulence following colistin adaptation in Klebsiella pneumoniae is strain-dependent rather than associated with specific mutations[J]. J Med Microbiol, 2017, 66(7): 959-964. DOI: 10.1099/jmm.0.000530.

43.Cain AK, Boinett CJ, Barquist L, et al. Morphological, genomic and transcriptomic responses of Klebsiella pneumoniae to the last-line antibiotic colistin[J]. Sci Rep, 2018, 8(1): 9868. DOI: 10.1038/s41598-018-28199-y.

44.Cheng YH, Lin TL, Lin YT, et al. Amino acid substitutions of CrrB responsible for resistance to colistin through CrrC in Klebsiella pneumoniae[J]. Antimicrob Agents Chemother, 2016, 60(6): 3709-3716. DOI: 10.1128/AAC.00009-16.

45.McConville TH, Annavajhala MK, Giddins MJ, et al. CrrB positively regulates high-level polymyxin resistance and virulence in Klebsiella pneumoniae[J]. Cell Rep, 2020, 33(4): 108313. DOI: 10.1016/j.celrep.2020.108313.

46.Jayol A, Nordmann P, André C, et al. Evaluation of three broth microdilution systems to determine colistin susceptibility of Gram-negative bacilli[J]. J Antimicrob Chemother, 2018, 73(5): 1272-1278. DOI: 10.1093/jac/dky012.

47.Pitt ME, Elliott AG, Cao MD, et al. Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae[J]. Microb Genom, 2018, 4(3): e000158. DOI: 10.1099/mgen.0.000158.

48.Gogry FA, Siddiqui MT, Sultan I, et al. Current update on intrinsic and acquired colistin resistance mechanisms in bacteria[J]. Front Med (Lausanne), 2021, 8: 677720. DOI: 10.3389/fmed.2021.677720.

49.Binsker U, Käsbohrer A, Hammerl JA. Global colistin use: a review of the emergence of resistant Enterobacterales and the impact on their genetic basis[J]. FEMS Microbiol Rev, 2022, 46(1): fuab049. DOI: 10.1093/femsre/fuab049.

50.Srinivasan VB, Vaidyanathan V, Mondal A, et al. Role of the two-component signal transduction system CpxAR in conferring cefepime and chloramphenicol resistance in Klebsiella pneumoniae NTUH-K2044[J]. PLoS One, 2012, 7(4): e33777. DOI: 10.1371/journal.pone.0033777.

51.Srinivasan VB, Venkataramaiah M, Mondal A, et al. Functional characterization of a novel outer membrane porin KpnO, regulated by PhoBR two-component system in Klebsiella pneumoniae NTUH-K2044[J]. PLoS One, 2012, 7(7): e41505. DOI: 10.1371/journal.pone.0041505.

52.Worthington RJ, Blackledge MS, Melander C. Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence[J]. Future Med Chem, 2013, 5(11): 1265-1284. DOI: 10.4155/fmc.13.58.

53.Milton ME, Minrovic BM, Harris DL, et al. Re-sensitizing multidrug resistant bacteria to antibiotics by targeting bacterial response regulators: characterization and comparison of interactions between 2-aminoimidazoles and the response regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp[J]. Front Mol Biosci, 2018, 5: 15. DOI: 10.3389/fmolb.2018.00015.

54.Bem AE, Velikova N, Pellicer MT, et al. Bacterial histidine kinases as novel antibacterial drug targets[J]. ACS Chem Biol, 2015, 10(1): 213-224. DOI: 10.1021/cb5007135.

55.Huang J, Li C, Song J, et al. Regulating polymyxin resistance in gram-negative bacteria: roles of two-component systems PhoPQ and PmrAB[J]. Future Microbiol, 2020, 15(6): 445-459. DOI: 10.2217/fmb-2019-0322.

56.Zhang K, Liu L, Yang M, et al. Reduced porin expression with EnvZ-OmpR, PhoPQ, BaeSR two-component system down-regulation in carbapenem resistance of Klebsiella pneumoniae based on proteomic analysis[J]. Microb Pathog, 2022,170: 105686. DOI: 10.1016/j.micpath.2022.105686.