Research progress on formation mechanism and eradication strategy of bacterial persisters

doi:10.3969/j.issn.1673-8640.2023.08.016

Abstract

Abstract:

Although bacterial persister has been found for a long time，they are rarely mentioned in anti-infective diagnosis and treatment. With the increasingly serious problem of antibiotic resistance and tolerance and the deepening of research，bacterial persistence has been found in most bacteria，and it is considered to be a cause of chronic infection and disease delay. The mechanism of bacterial persister formation involves many cell life processes，but it is still not completely clear. There is a consensus on the treatment strategy for bacterial persisters. This review focuses on the mechanism research of bacterial persisters and the treatment strategies in the recent years，so as to solve the major challenge in the treatment of chronic infectious diseases.

Key words: Bacterial persister, Mechanism, Eradication, Anti-infection, Drug resistance

CLC Number:

R446.1

WANG Chao, ZHAO Yu. Research progress on formation mechanism and eradication strategy of bacterial persisters[J]. Laboratory Medicine, 2023, 38(8): 790-795.

Figures/Tables 1

References 42

[1]	BALABAN N Q, HELAINE S, LEWIS K, et al. Definitions and guidelines for research on antibiotic persistence[J]. Nat Rev Microbiol, 2019, 17(7):441-448. DOI PMID
[2]	HUEMER M, MAIRPADY SHAMBAT S, BERGADA-PIJUAN J, et al. Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success[J]. Proc Natl Acad Sci U S A, 2021, 118(7):e2014920118.
[3]	PEYRUSSON F, VARET H, NGUYEN T K, et al. Intracellular Staphylococcus aureus persisters upon antibiotic exposure[J]. Nat Commun, 2020, 11(1):2200. DOI
[4]	WILMAERTS D, WINDELS E M, VERSTRAETEN N, et al. General mechanisms leading to persister formation and awakening[J]. Trends Genet, 2019, 35(6):401-411. DOI PMID
[5]	BAKKEREN E, DIARD M, HARDT W D. Evolutionary causes and consequences of bacterial antibiotic persistence[J]. Nat Rev Microbiol, 2020, 18(9):479-490. DOI PMID
[6]	HARMS A, BRODERSEN D E, MITARAI N, et al. Toxins,targets,and triggers:an overview of toxin-antitoxin biology[J]. Mol Cell, 2018, 70(5):768-784. DOI URL
[7]	TALWAR S, PANDEY M, SHARMA C, et al. Role of VapBC12 toxin-antitoxin locus in cholesterol-induced mycobacterial persistence[J]. mSystems, 2020, 5(6):e00855.
[8]	PINEL-MARIE M L, BRIELLE R, RIFFAUD C, et al. RNA antitoxin SprF1 binds ribosomes to attenuate translation and promote persister cell formation in Staphylococcus aureus[J]. Nat Microbiol, 2021, 6(2):209-220. DOI
[9]	ZHOU J, LI S, LI H, et al. Identification of a toxin-antitoxin system that contributes to persister formation by reducing NAD in Pseudomonas aeruginosa[J]. Microorganisms, 2021, 9(4):753. DOI URL
[10]	GERDES K, BÆRENTSEN R, BRODERSEN D E. Phylogeny reveals novel hipa-homologous kinase families and toxin-antitoxin gene organizations[J]. mBio, 2021, 12(3):e0105821. DOI URL
[11]	CHOWDHURY N, KWAN B W, WOOD T K. Persistence increases in the absence of the alarmone guanosine tetraphosphate by reducing cell growth[J]. Sci Rep, 2016, 6:20519. DOI PMID
[12]	VÖLZING K G, BRYNILDSEN M P. Stationary-phase persisters to ofloxacin sustain DNA damage and require repair systems only during recovery[J]. mBio, 2015, 6(5):e00731.
[13]	LOBRITZ M A, BELENKY P, PORTER C B, et al. Antibiotic efficacy is linked to bacterial cellular respiration[J]. Proc Natl Acad Sci U S A, 2015, 112(27):8173-8180. DOI URL
[14]	VOGWILL T, COMFORT A C, FURIÓ V, et al. Persistence and resistance as complementary bacterial adaptations to antibiotics[J]. J Evol Biol, 2016, 29(6):1223-1233. DOI URL
[15]	VAN DEN BERGH B, FAUVART M, MICHIELS J. Formation,physiology,ecology,evolution and clinical importance of bacterial persisters[J]. FEMS Microbiol Rev, 2017, 41(3):219-251. DOI URL
[16]	BROWNING A P, SHARP J A, MAPDER T, et al. Persistence as an optimal hedging strategy[J]. Biophys J, 2021, 120(1):133-142. DOI PMID
[17]	VAN DEN BERGH B, MICHIELS J E, MICHIELS J. Experimental evolution of Escherichia coli persister levels using cyclic antibiotic treatments[J]. Methods Mol Biol, 2016, 1333:131-143.
[18]	GHOSH A, BALTEKIN Ö, WÄNESKOG M, et al. Contact-dependent growth inhibition induces high levels of antibiotic-tolerant persister cells in clonal bacterial populations[J]. EMBO J, 2018, 37(9):e98026. DOI URL
[19]	MURAWSKI A M, BRYNILDSEN M P. Ploidy is an important determinant of fluoroquinolone persister survival[J]. Curr Biol, 2021, 31(10):2039-2050. DOI URL
[20]	XU Y, LIU S, ZHANG Y, et al. DNA adenine methylation is involved in persister formation in E.coli[J]. Microbiol Res, 2021, 246:126709. DOI URL
[21]	KIM W, ZHU W, HENDRICKS G L, et al. A new class of synthetic retinoid antibiotics effective against bacterial persisters[J]. Nature, 2018, 556(7699):103-107. DOI URL
[22]	XIAO X, ZHANG S, CHEN S, et al. An alpha/beta chimeric peptide molecular brush for eradicating MRSA biofilms and persister cells to mitigate antimicrobial resistance[J]. Biomater Sci, 2020, 8(24):6883-6889. DOI URL
[23]	ANTONOPLIS A, ZANG X, HUTTNER M A, et al. A dual-function antibiotic-transporter conjugate exhibits superior activity in sterilizing MRSA biofilms and killing persister cells[J]. J Am Chem Soc, 2018, 140(47):16140-16151. DOI PMID
[24]	SHATALIN K, NUTHANAKANTI A, KAUSHIK A, et al. Inhibitors of bacterial H₂S biogenesis targeting antibiotic resistance and tolerance[J]. Science, 2021, 372(6547):1169-1175. DOI URL
[25]	LIEBENS V, DEFRAINE V, KNAPEN W, et al. Identification of 1-(( 2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol,a novel antibacterial compound active against persisters of Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother, 2017, 61(9):e00836.
[26]	ABOUELHASSAN Y, BASAK A, YOUSAF H, et al. Identification of N-arylated NH125 analogues as rapid eradicating agents against MRSA persister cells and potent biofilm killers of Gram-positive pathogens[J]. Chembiochem, 2017, 18(4):352-357. DOI PMID
[27]	ABOUELHASSAN Y, ZHANG P, DING Y, et al. Rapid kill assessment of an N-arylated NH125 analogue against drug-resistant microorganisms[J]. Medchemcomm, 2019, 10(5):712-716. DOI URL
[28]	NARAYANASWAMY V P, KEAGY L L, DURIS K, et al. Novel glycopolymer eradicates antibiotic- and CCCP-induced persister cells in Pseudomonas aeruginosa[J]. Front Microbiol, 2018, 9:1724. DOI URL
[29]	SIMONSON A W, UMSTEAD T M, LAWANPRASERT A, et al. Extracellular matrix-inspired inhalable aerogels for rapid clearance of pulmonary tuberculosis[J]. Biomaterials, 2021, 273:120848. DOI URL
[30]	CHUNG E S, KO K S. Eradication of persister cells of Acinetobacter baumannii through combination of colistin and amikacin antibiotics[J]. J Antimicrob Chemother, 2019, 74(5):1277-1283. DOI URL
[31]	BAEK M S, CHUNG E S, JUNG D S, et al. Effect of colistin-based antibiotic combinations on the eradication of persister cells in Pseudomonas aeruginosa[J]. J Antimicrob Chemother, 2020, 75(4):917-924. DOI URL
[32]	ZHENG E J, STOKES J M, COLLINS J J. Eradicating bacterial persisters with combinations of strongly and weakly metabolism-dependent antibiotics[J]. Cell Chem Biol, 2020, 27(12):1544-1552. DOI PMID
[33]	LU C H, SHIAU C W, CHANG Y C, et al. SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance[J]. J Antimicrob Chemother, 2021, 76(8):2049-2056. DOI URL
[34]	CRUZ-MUÑIZ M Y, LÓPEZ-JACOME L E, HERNÁNDEZ-DURÁN M, et al. Repurposing the anticancer drug mitomycin C for the treatment of persistent Acinetobacter baumannii infections[J]. Int J Antimicrob Agents, 2017, 49(1):88-92. DOI URL
[35]	STOKES J M, YANG K, SWANSON K, et al. A deep learning approach to antibiotic discovery[J]. Cell, 2020, 180(4):688-702. DOI PMID
[36]	DEFRAINE V, FAUVART M, MICHIELS J. Fighting bacterial persistence:current and emerging anti-persister strategies and therapeutics[J]. Drug Resist Updat, 2018, 38:12-26. DOI URL
[37]	MOK W W K, BRYNILDSEN M P. Timing of DNA damage responses impacts persistence to fluoroquinolones[J]. Proc Natl Acad Sci U S A, 2018, 115(27):E6301-E6309.
[38]	CHEVERTON A M, GOLLAN B, PRZYDACZ M, et al. A Salmonella toxin promotes persister formation through acetylation of tRNA[J]. Mol Cell, 2016, 63(1):86-96. DOI URL
[39]	KIM J S, YAMASAKI R, SONG S, et al. Single cell observations show persister cells wake based on ribosome content[J]. Environ Microbiol, 2018, 20(6):2085-2098. DOI URL
[40]	ALLEGRETTA G, MAURER C K, EBERHARD J, et al. In-depth profiling of MvfR-regulated small molecules in Pseudomonas aeruginosa after quorum sensing inhibitor treatment[J]. Front Microbiol, 2017, 8:924. DOI URL
[41]	TKACHENKO A G, KASHEVAROVA N M, SIDOROV R Y, et al. A synthetic diterpene analogue inhibits mycobacterial persistence and biofilm formation by targeting(p)ppGpp synthetases[J]. Cell Chem Biol, 2021, 28(10):1420-1432. DOI URL
[42]	LI T, YIN N, LIU H, et al. Novel inhibitors of toxin hipa reduce multidrug tolerant persisters[J]. ACS Med Chem Lett, 2016, 7(5):449-453. DOI PMID

名称	类型	作用机制	作用菌种	参考文献
CD437和CD1530	合成类视黄醇	破坏脂质双层	耐甲氧西林金黄色葡萄球菌持留菌	[21]
α/β嵌合多肽分子刷	宿主防御肽聚合物模拟物	干扰细胞膜，增加ROS水平	耐甲氧西林金黄色葡萄球菌生物膜和持留菌	[22]
万古霉素-D-八精氨酸	双功能抗菌药物-转运蛋白偶联物	在分子转运蛋白的协助下，万古霉素阻止细胞壁组装，抑制胱硫氨酸γ裂解酶	耐甲氧西林金黄色葡萄球菌生物膜和持留菌	[23]
NL1、NL2、NL3	小分子酶抑制剂	在分子转运蛋白的协助下，万古霉素阻止细胞壁组装，抑制胱硫氨酸γ裂解酶	金黄色葡萄球菌持留菌和铜绿假单胞菌持留菌	[24]
SPI009	小分子化合物	广泛破坏生物膜，增强协同抗菌药物活性	铜绿假单胞菌持留菌	[25]
N-芳基化NH125类似物1	膜活性双亲性化合物，季铵阳离子	引起细胞膜去极化，破坏脂质双层	耐甲氧西林金黄色葡萄球菌持留菌	[26-27]
聚（乙酰，精氨酰）氨基葡萄糖	大分子阳离子含糖聚合物	增加细胞膜通透性，引起细胞膜去极化	铜绿假单胞菌持留菌	[28]

名称	类型	作用机制	作用菌种	参考文献
CD437和CD1530	合成类视黄醇	破坏脂质双层	耐甲氧西林金黄色葡萄球菌持留菌	[21]
α/β嵌合多肽分子刷	宿主防御肽聚合物模拟物	干扰细胞膜，增加ROS水平	耐甲氧西林金黄色葡萄球菌生物膜和持留菌	[22]
万古霉素-D-八精氨酸	双功能抗菌药物-转运蛋白偶联物	在分子转运蛋白的协助下，万古霉素阻止细胞壁组装，抑制胱硫氨酸γ裂解酶	耐甲氧西林金黄色葡萄球菌生物膜和持留菌	[23]
NL1、NL2、NL3	小分子酶抑制剂	在分子转运蛋白的协助下，万古霉素阻止细胞壁组装，抑制胱硫氨酸γ裂解酶	金黄色葡萄球菌持留菌和铜绿假单胞菌持留菌	[24]
SPI009	小分子化合物	广泛破坏生物膜，增强协同抗菌药物活性	铜绿假单胞菌持留菌	[25]
N-芳基化NH125类似物1	膜活性双亲性化合物，季铵阳离子	引起细胞膜去极化，破坏脂质双层	耐甲氧西林金黄色葡萄球菌持留菌	[26-27]
聚（乙酰，精氨酰）氨基葡萄糖	大分子阳离子含糖聚合物	增加细胞膜通透性，引起细胞膜去极化	铜绿假单胞菌持留菌	[28]