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Journal of microbiology (Seoul, Korea)
Mar, 2023;61 (3): 331-341.

Membrane Proteins as a Regulator for Antibiotic Persistence in Gram-Negative Bacteria.

Jia Xin Yee, Juhyun Kim, Jinki Yeom
Author Information
  1. Jia Xin Yee: Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore.
  2. Juhyun Kim: School of Life Science, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea. juhyunkim@knu.ac.kr.
  3. Jinki Yeom: Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore. jinki.yeom@snu.ac.kr.
PMID: 36800168 DOI: 10.1007/s12275-023-00024-w

Abstract

Antibiotic treatment failure threatens our ability to control bacterial infections that can cause chronic diseases. Persister bacteria are a subpopulation of physiological variants that becomes highly tolerant to antibiotics. Membrane proteins play crucial roles in all living organisms to regulate cellular physiology. Although a diverse membrane component involved in persistence can result in antibiotic treatment failure, the regulations of antibiotic persistence by membrane proteins has not been fully understood. In this review, we summarize the recent advances in our understanding with regards to membrane proteins in Gram-negative bacteria as a regulator for antibiotic persistence, highlighting various physiological mechanisms in bacteria.

Keywords

Antibiotics Gram-negative bacteria Membrane proteins Pathogen Persistence

References

  1. Ago, R., & Shiomi, D. (2019). RodZ: A key-player in cell elongation and cell division in Escherichia coli. AIMS Microbiology, 5, 358–367. [PMID: 31915748]
  2. Baek, S. H., Li, A. H., & Sassetti, C. M. (2011). Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biology, 9, e1001065. [PMID: 21629732]
  3. Baker, T. A., Funnell, B. E., & Kornberg, A. (1987). Helicase action of dnaB protein during replication from the Escherichia coli chromosomal origin in vitro. Journal Biological Chemistry, 262, 6877–6885. [DOI: 10.1016/S0021-9258(18)48326-3]
  4. Balaban, N. Q., Helaine, S., Lewis, K., Ackermann, M., Aldridge, B., Andersson, D. I., Brynildsen, M. P., Bumann, D., Camilli, A., Collins, J. J., et al. (2019). Definitions and guidelines for research on antibiotic persistence. Nature Reviews Microbiology, 17, 441–448. [PMID: 30980069]
  5. Balaban, N. Q., & Liu, J. (2019). Evolution under antibiotic treatments: Interplay between antibiotic persistence, tolerance, and resistance. In K. Lewis (Ed.), Persister cells and infectious disease (pp. 1–17). Cham: Springer.
  6. Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. (2004). Bacterial persistence as a phenotypic switch. Science, 305, 1622–1625. [PMID: 15308767]
  7. Bittner, L. M., Arends, J., & Narberhaus, F. (2017). When, how and why? Regulated proteolysis by the essential FtsH protease in Escherichia coli. Biological Chemistry, 398, 625–635. [PMID: 28085670]
  8. Brauner, A., Fridman, O., Gefen, O., & Balaban, N. Q. (2016). Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nature Reviews Microbiology, 14, 320–330. [PMID: 27080241]
  9. Chatterji, D., & Ojha, A. K. (2001). Revisiting the stringent response, ppGpp and starvation signaling. Current Opinion in Microbiology, 4, 160–165. [PMID: 11282471]
  10. Cheverton, A. M., Gollan, B., Przydacz, M., Wong, C. T., Mylona, A., Hare, S. A., & Helaine, S. (2016). A Salmonella toxin promotes persister formation through acetylation of tRNA. Molecular Cell, 63, 86–96. [PMID: 27264868]
  11. Chong, S., Chen, C., Ge, H., & Xie, X. S. (2014). Mechanism of transcriptional bursting in bacteria. Cell, 158, 314–326. [PMID: 25036631]
  12. Culp, E., & Wright, G. D. (2017). Bacterial proteases, untapped antimicrobial drug targets. The Journal of Antibiotics, 70, 366–377. [PMID: 27899793]
  13. Dörr, T., Lewis, K., & Vulić, M. (2009). SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genetics, 5, e1000760. [PMID: 20011100]
  14. Erbse, A., Schmidt, R., Bornemann, T., Schneider-Mergener, J., Mogk, A., Zahn, R., Dougan, D. A., & Bukau, B. (2006). ClpS is an essential component of the N-end rule pathway in Escherichia coli. Nature, 439, 753–756. [PMID: 16467841]
  15. Fernández De Henestrosa, A. R., Ogi, T., Aoyagi, S., Chafin, D., Hayes, J. J., Ohmori, H., & Woodgate, R. (2000). Identification of additional genes belonging to the LexA regulon in Escherichia coli. Molecular Microbiology, 35, 1560–1572. [PMID: 10760155]
  16. Fisher, R. A., Gollan, B., & Helaine, S. (2017). Persistent bacterial infections and persister cells. Nature Reviews Microbiology, 15, 453–464. [PMID: 28529326]
  17. Garvey, N., St John, A. C., & Witkin, E. M. (1985). Evidence for RecA protein association with the cell membrane and for changes in the levels of major outer membrane proteins in SOS-induced Escherichia coli cells. Journal of Bacteriology, 163, 870–876. [PMID: 3897198]
  18. Gerdes, K., & Wagner, E. G. H. (2007). RNA antitoxins. Current Opinion in Microbiology, 10, 117–124. [PMID: 17376733]
  19. Germain, E., Castro-Roa, D., Zenkin, N., & Gerdes, K. (2013). Molecular mechanism of bacterial persistence by HipA. Molecular Cell, 52, 248–254. [PMID: 24095282]
  20. Gur, E., Biran, D., & Ron, E. Z. (2011). Regulated proteolysis in Gram-negative bacteria – How and when? Nature Reviews Microbiology, 9, 839–848. [PMID: 22020261]
  21. Harms, A., Maisonneuve, E., & Gerdes, K. (2016). Mechanisms of bacterial persistence during stress and antibiotic exposure. Science, 354, aaf4268. [PMID: 27980159]
  22. Hauryliuk, V., Atkinson, G. C., Murakami, K. S., Tenson, T., & Gerdes, K. (2015). Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nature Reviews Microbiology, 13, 298–309. [PMID: 25853779]
  23. Humbard, M. A., Surkov, S., De Donatis, G. M., Jenkins, L. M., & Maurizi, M. R. (2013). The N-degradome of Escherichia coli. The Journal of Biological Chemistry, 288, 28913–28924. [PMID: 23960079]
  24. Irving, S. E., Choudhury, N. R., & Corrigan, R. M. (2021). The stringent response and physiological roles of (pp)pGpp in bacteria. Nature Reviews Microbiology, 19, 256–271. [PMID: 33149273]
  25. Jensen, H. M., Eng, T., Chubukov, V., Herbert, R. A., & Mukhopadhyay, A. (2017). Improving membrane protein expression and function using genomic edits. Scientific Reports, 7, 13030. [PMID: 29026162]
  26. Jung, S. H., Ryu, C. M., & Kim, J. S. (2019). Bacterial persistence: Fundamentals and clinical importance. Journal of Microbiology, 57, 829–835. [PMID: 31463787]
  27. Kanjee, U., Ogata, K., & Houry, W. A. (2012). Direct binding targets of the stringent response alarmone (p)ppGpp. Molecular Microbiology, 85, 1029–1043. [PMID: 22812515]
  28. Kirstein, J., Hoffmann, A., Lilie, H., Schmidt, R., Rübsamen-Waigmann, H., Brötz-Oesterhelt, H., Mogk, A., & Turgay, K. (2009). The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease. EMBO Molecular Medicine, 1, 37–49. [PMID: 20049702]
  29. Kohanski, M. A., Dwyer, D. J., & Collins, J. J. (2010). How antibiotics kill bacteria: From targets to networks. Nature Reviews Microbiology, 8, 423–435. [PMID: 20440275]
  30. Korch, S. B., Henderson, T. A., & Hill, T. M. (2003). Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Molecular Microbiology, 50, 1199–1213. [PMID: 14622409]
  31. Lee, E. J., Pontes, M. H., & Groisman, E. A. (2013). A bacterial virulence protein promotes pathogenicity by inhibiting the bacterium’s own FF ATP synthase. Cell, 154, 146–156. [PMID: 23827679]
  32. Levin-Reisman, I., Ronin, I., Gefen, O., Braniss, I., Shoresh, N., & Balaban, N. Q. (2017). Antibiotic tolerance facilitates the evolution of resistance. Science, 355, 826–830. [PMID: 28183996]
  33. Liu, L. F., & Wang, J. C. (1987). Supercoiling of the DNA template during transcription. Proceedings of the National Academy of Sciences of the United States of America, 84, 7024–7027. [PMID: 2823250]
  34. Masuda, H., Tan, Q., Awano, N., Wu, K. P., & Inouye, M. (2012). YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. Molecular Microbiology, 84, 979–989. [PMID: 22515815]
  35. May, K. L., & Grabowicz, M. (2018). The bacterial outer membrane is an evolving antibiotic barrier. Proceedings of the National Academy of Sciences of the United States of America, 115, 8852–8854. [PMID: 30139916]
  36. Mechold, U., Potrykus, K., Murphy, H., Murakami, K. S., & Cashel, M. (2013). Differential regulation by ppGpp versus pppGpp in Escherichia coli. Nucleic Acids Research, 41, 6175–6189. [PMID: 23620295]
  37. Moussouni, M., Nogaret, P., Garai, P., Ize, B., Vivès, E., & Blanc-Potard, A. B. (2019). Activity of a synthetic peptide targeting MgtC on Pseudomonas aeruginosa intramacrophage survival and biofilm formation. Frontiers in Cellular and Infection Microbiology, 9, 84. [PMID: 31001488]
  38. Olvera, M. R., Garai, P., Mongin, G., Vives, E., Gannoun-Zaki, L., & Blanc-Potard, A. B. (2019). Synthetic hydrophobic peptides derived from MgtR weaken Salmonella pathogenicity and work with a different mode of action than endogenously produced peptides. Scientific Reports, 9, 15253. [PMID: 31649255]
  39. Page, R., & Peti, W. (2016). Toxin-antitoxin systems in bacterial growth arrest and persistence. Nature Chemical Biology, 12, 208–214. [PMID: 26991085]
  40. Pantua, H., Skippington, E., Braun, M. G., Noland, C. L., Diao, J. Y., Peng, Y. T., Gloor, S. L., Yan, D. H., Kang, L., Katakam, A. K., et al. (2020). Unstable mechanisms of resistance to inhibitors of Escherichia coli lipoprotein signal peptidase. mBio, 11, e02018-20. [PMID: 32900806]
  41. Pedersen, K., & Gerdes, K. (1999). Multiple hok genes on the chromosome of Escherichia coli. Molecular Microbiology, 32, 1090–1102. [PMID: 10361310]
  42. Piddock, L. J. V. (2006). Multidrug-resistance efflux pumps? not just for resistance. Nature Reviews Microbiology, 4, 629–636. [PMID: 16845433]
  43. Podlesek, Z., & Žgur Bertok, D. Ž. (2020). The DNA damage inducible SOS response is a key player in the generation of bacterial persister cells and population wide tolerance. Frontiers in Microbiology, 11, 1785. [PMID: 32849403]
  44. Pontes, M. H., & Groisman, E. A. (2019). Slow growth determines nonheritable antibiotic resistance in Salmonella enterica. Science Signaling, 12, eaax3938. [PMID: 31363068]
  45. Pontes, M. H., Yeom, J., & Groisman, E. A. (2016). Reducing ribosome biosynthesis promotes translation during low Mg stress. Molecular Cell, 64, 480–492. [PMID: 27746019]
  46. Pu, Y., Li, Y., Jin, X., Tian, T., Ma, Q., Zhao, Z., Lin, S., Chen, Z., Li, B., Yao, G., et al. (2019). ATP-dependent dynamic protein aggregation regulates bacterial dormancy depth critical for antibiotic tolerance. Molecular Cell, 73, 143–156. [PMID: 30472191]
  47. Pu, Y., Zhao, Z., Li, Y., Zou, J., Ma, Q., Zhao, Y., Ke, Y., Zhu, Y., Chen, H., Baker, M. A. B., et al. (2016). Enhanced efflux activity facilitates drug tolerance in dormant bacterial cells. Molecular Cell, 62, 284–294. [PMID: 27105118]
  48. Roghanian, M., Semsey, S., Løbner-Olesen, A., & Jalalvand, F. (2019). (p)ppGpp-mediated stress response induced by defects in outer membrane biogenesis and ATP production promotes survival in Escherichia coli. Scientific Reports, 9, 2934. [PMID: 30814571]
  49. Roostalu, J., Jõers, A., Luidalepp, H., Kaldalu, N., & Tenson, T. (2008). Cell division in Escherichia coli cultures monitored at single cell resolution. BMC Microbiology, 8, 68. [PMID: 18430255]
  50. Schramm, F. D., Schroeder, K., & Jonas, K. (2020). Protein aggregation in bacteria. FEMS Microbiology Reviews, 4, 54–72. [DOI: 10.1093/femsre/fuz026]
  51. Scott, M., & Hwa, T. (2011). Bacterial growth laws and their applications. Current Opinion in Biotechnology, 22, 559–565. [PMID: 21592775]
  52. Scott, M., Klumpp, S., Mateescu, E. M., & Hwa, T. (2014). Emergence of robust growth laws from optimal regulation of ribosome synthesis. Molecular Systems Biology, 10, 747. [PMID: 25149558]
  53. Senior, A. E. (1990). The proton-translocating ATPase of Escherichia coli. Annual Review of Biophysics and Biophysical Chemistry, 19, 7–41. [PMID: 2141983]
  54. Shan, Y., Brown Gandt, A., Rowe, S. E., Deisinger, J. P., Conlon, B. P., & Lewis, K. (2017). ATP-dependent persister formation in Escherichia coli. mBio, 8, e02267-16. [PMID: 28174313]
  55. Silhavy, T. J., Kahne, D., & Walker, S. (2010). The bacterial cell envelope. Cold Spring Harbor Perspectives in Biology, 2, a000414. [PMID: 20452953]
  56. Silva, C. D., Hajihosseini, A., Myrick, J., Nole, J., Louie, A., Schmidt, S., & Drusano, G. L. (2018). Effect of linezolid plus bedaquiline against Mycobacterium tuberculosis in log phase, acid phase, and nonreplicating-persister phase in an in vitro assay. Antimicrobial Agents and Chemotherapy, 62, e00856-18.
  57. Smani, Y., Fàbrega, A., Roca, I., Sánchez-Encinales, V., Vila, J., & Pachón, J. (2014). Role of OmpA in the multidrug resistance phenotype of Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy, 58, 1806–1808. [PMID: 24379205]
  58. Thisted, T., Sørensen, N. S., Wagner, E. G., & Gerdes, K. (1994). Mechanism of post-segregational killing: Sok antisense RNA interacts with Hok mRNA via its 5′-end single-stranded leader and competes with the 3′-end of Hok mRNA for binding to the mok translational initiation region. EMBO Journal, 13, 1960–1968. [PMID: 8168493]
  59. Tommassen, J. (2010). Assembly of outer-membrane proteins in bacteria and mitochondria. Microbiology, 156, 2587–2596. [PMID: 20616105]
  60. van der Heijden, J., Reynolds, L. A., Deng, W., Mills, A., Scholz, R., Imami, K., Foster, L. J., Duong, F., & Finlay, B. B. (2016). Salmonella rapidly regulates membrane permeability to survive oxidative stress. mBio, 7, e01238-16. [PMID: 27507830]
  61. Verstraeten, N., Knapen, W. J., Kint, C. I., Liebens, V., Van den Bergh, B., Dewachter, L., Michiels, J. E., Fu, Q., David, C. C., Fierro, A. C., et al. (2015). Obg and membrane depolarization are part of a microbial bet-hedging strategy that leads to antibiotic tolerance. Molecular Cell, 59, 9–21. [PMID: 26051177]
  62. Vogel, J., Argaman, L., Wagner, E. G. H., & Altuvia, S. (2004). The small RNA IstR inhibits synthesis of an SOS-induced toxic peptide. Current Biology, 14, 2271–2276. [PMID: 15620655]
  63. Wilmaerts, D., Dewachter, L., De Loose, P.-J., Bollen, C., Verstraeten, N., & Michiels, J. (2019). HokB monomerization and membrane repolarization control persister awakening. Molecular Cell, 75, 1031–1042. [PMID: 31327636]
  64. Yeom, J., Gao, X., & Groisman, E. A. (2018). Reduction in adaptor amounts establishes degradation hierarchy among protease substrates. Proceedings of the National Academy of Sciences of the United States of America, 115, E4483–E4492. [PMID: 29686082]
  65. Yeom, J., & Groisman, E. A. (2019). Activator of one protease transforms into inhibitor of another in response to nutritional signals. Genes & Development, 33, 1280–1292. [DOI: 10.1101/gad.325241.119]
  66. Yeom, J., & Groisman, E. A. (2021a). Low cytoplasmic magnesium increases the specificity of the lon and ClpAP proteases. Journal of Bacteriology, 203, e00143-21. [PMID: 33941609]
  67. Yeom, J., & Groisman, E. A. (2021b). Reduced ATP-dependent proteolysis of functional proteins during nutrient limitation speeds the return of microbes to a growth state. Science Signaling, 14, eabc4235. [PMID: 33500334]
  68. Zgurskaya, H. I., López, C. A., & Gnanakaran, S. (2015). Permeability barrier of Gram-negative cell envelopes and approaches to bypass it. ACS Infectious Diseases, 1, 512–522. [PMID: 26925460]
  69. Zhu, M., & Dai, X. (2019). Growth suppression by altered (p)ppGpp levels results from non-optimal resource allocation in Escherichia coli. Nucleic Acids Research, 47, 4684–4693. [PMID: 30916318]

MeSH Term

Humans
Anti-Bacterial Agents
Membrane Proteins
Bacteria
Gram-Negative Bacteria
Bacterial Infections

Chemicals

Anti-Bacterial Agents
Membrane Proteins
Journal Article Review
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