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Antibiotics: Precious Goods in Changing Times

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Antibiotics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2601))

Abstract

Antibiotics represent a first line of defense of diverse microorganisms, which produce and use antibiotics to counteract natural enemies or competitors for nutritional resources in their nearby environment. For antimicrobial activity, nature has invented a great variety of antibiotic modes of action that involve the perturbation of essential bacterial structures or biosynthesis pathways of macromolecules such as the bacterial cell wall, DNA, RNA, or proteins, thereby threatening the specific microbial lifestyle and eventually even survival. However, along with highly inventive modes of antibiotic action, nature also developed a comparable set of resistance mechanisms that help the bacteria to circumvent antibiotic action. Microorganisms have evolved specific adaptive responses that allow to appropriately react to the presence of antimicrobial agents, thereby ensuring survival during antimicrobial stress. In times of rapid development and spread of antibiotic (multi-)resistance, new resistance-breaking strategies to counteract bacterial infections are desperately needed. This chapter is an update to Chapter 1 of the first edition of this book and intends to give an overview of common antibiotics and their target pathways. It will also present examples for new antibiotics with novel modes of action, illustrating that nature’s repertoire of innovative new antimicrobial agents has not been fully exploited yet, and we still might find new drugs that help to evade established antimicrobial resistance strategies.

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References

  1. WHO (2015) http://www.who.int/mediacentre/factsheets/fs194/en/. Accessed 29 June 2022

  2. Matos C, Sass P (2020) Tackling antimicrobial resistance by exploring new mechanisms of antibiotic action. Future Microbiol 15:703–708

    Article  Google Scholar 

  3. CDC (2011) Antimicrobial Resistance Posing Growing Health Threat. Centers for Disease Control and Prevention. http://www.cdc.gov/media/releases/2011/p0407_antimicrobialresistance.html. Accessed 29 June 2022

    Google Scholar 

  4. AMR-review (2016) 22nd March 2016- Infection Prevention Control and Surveillance: limiting the development and spread of drug resistance. http://amr-review.org/. Accessed 29 June 2022

  5. Resistance RoA (2016) Tackling drug-resistant infections globally: final report and recommendations. https://amr-review.org. Accessed 29 June 2022

  6. Nature E (2018) Wanted: a reward for antibiotic development. Nat Biotechnol 36:555

    Google Scholar 

  7. Cooper MA, Shlaes D (2011) Fix the antibiotics pipeline. Nature 472(7341):32

    Google Scholar 

  8. EU-Commission (2008) Innovative Medicines Initiative (IMI). https://www.imi.europa.eu. Accessed 29 June 2022

  9. EU-Commission (2011) Action plan against the rising threats from Antimicrobial Resistance. https://health.ec.europa.eu/system/files/2020-01/communication_amr_2011_748_en_0.pdf. Accessed 29 June 2022

  10. EU-Commission (2017) A European One Health Action Plan against Antimicrobial Resistance (AMR). https://health.ec.europa.eu/system/files/2020-01/amr_2017_action-plan_0.pdf. Accessed 29 June 2022

  11. EU-Commission (2011) New Drugs for Bad Bugs (ND4BB). https://www.imi.europa.eu/projects-results/project-factsheets/nd4bb. Accessed 29 June 2022

  12. EU-Commission (2011) Joint Programming Initiative on AMR (JPIAMR). https://www.jpiamr.eu. Accessed 29 June 2022

  13. America IDSo (2010) The 10 × ‘20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis 50 (8):1081-1083

    Google Scholar 

  14. Partnership GGARD GARDP. Global Antibiotic Research & Development Partnership. https://www.gardp.org. Accessed 29 June 2022

  15. FOR854 (2008) https://gepris.dfg.de/gepris/projekt/33421847. Accessed 29 June 2022

  16. DZIF (2010) http://www.dzif.de/en/research/novel_antiinfectives/. Accessed 29 June 2022

  17. CMFI CoE controlling microbes to fight infections. https://uni-tuebingen.de/en/research/core-research/cluster-of-excellence-cmfi/. Accessed 29 June 2022

  18. Transregional Collaborative Research Center TRR261. https://trr261.de. Accessed 29 June 2022

  19. GRC (2016) Gordon Research Conference: new antibacterial discovery & development. https://www.grc.org/new-antibacterial-discovery-and-development-conference/default.aspx. Accessed 29 June 2022

  20. Sass P (2017) Antibiotics: precious goods in changing times. Methods Mol Biol 1520:3–22

    Google Scholar 

  21. Russell AD (2003) Similarities and differences in the responses of microorganisms to biocides. J Antimicrob Chemother 52(5):750–763

    Article  PubMed  CAS  Google Scholar 

  22. Aminov RI (2009) The role of antibiotics and antibiotic resistance in nature. Environ Microbiol 11(12):2970–2988

    Article  PubMed  CAS  Google Scholar 

  23. Yang D, Biragyn A, Kwak LW, Oppenheim JJ (2002) Mammalian defensins in immunity: more than just microbicidal. Trends Immunol 23(6):291–296

    Article  PubMed  CAS  Google Scholar 

  24. Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ (2004) Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu Rev Immunol 22:181–215

    Article  PubMed  Google Scholar 

  25. Bowdish DM, Davidson DJ, Hancock RE (2005) A re-evaluation of the role of host defence peptides in mammalian immunity. Curr Protein Pept Sci 6(1):35–51

    Article  PubMed  CAS  Google Scholar 

  26. Kodani S, Hudson ME, Durrant MC, Buttner MJ, Nodwell JR, Willey JM (2004) The SapB morphogen is a lantibiotic-like peptide derived from the product of the developmental gene ramS in Streptomyces coelicolor. Proc Natl Acad Sci U S A 101(31):11448–11453

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kleerebezem M (2004) Quorum sensing control of lantibiotic production; nisin and subtilin autoregulate their own biosynthesis. Peptides 25(9):1405–1414

    Article  PubMed  CAS  Google Scholar 

  28. Schmitz S, Hoffmann A, Szekat C, Rudd B, Bierbaum G (2006) The lantibiotic mersacidin is an autoinducing peptide. Appl Environ Microbiol 72(11):7270–7277

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Navarre WW, Schneewind O (1999) Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol Mol Biol Rev 63(1):174–229

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. van Heijenoort J (2001) Formation of the glycan chains in the synthesis of bacterial peptidoglycan. Glycobiology 11(3):25–36

    Article  Google Scholar 

  31. Pages JM, James CE, Winterhalter M (2008) The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 6(12):893–903

    Article  PubMed  CAS  Google Scholar 

  32. Coyette J, van der Ende A (2008) Peptidoglycan: the bacterial Achilles heel. FEMS Microbiol Rev 32(2):147–148

    Article  PubMed  CAS  Google Scholar 

  33. Schneider T, Sahl HG (2010) An oldie but a goodie – cell wall biosynthesis as antibiotic target pathway. Int J Med Microbiol 300(2-3):161–169

    Article  PubMed  CAS  Google Scholar 

  34. Yocum RR, Rasmussen JR, Strominger JL (1980) The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase. J Biol Chem 255(9):3977–3986

    Article  PubMed  CAS  Google Scholar 

  35. Yocum RR, Waxman DJ, Rasmussen JR, Strominger JL (1979) Mechanism of penicillin action: penicillin and substrate bind covalently to the same active site serine in two bacterial D-alanine carboxypeptidases. Proc Natl Acad Sci U S A 76(6):2730–2734

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Neuhaus FC, Lynch JL (1964) The enzymatic synthesis of D-alanyl-D-alanine. 3. On the inhibition of D-alanyl-D-alanine synthetase by the antibiotic D-cycloserine. Biochemistry 3:471–480

    Article  PubMed  CAS  Google Scholar 

  37. Lambert MP, Neuhaus FC (1972) Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W. J Bacteriol 110(3):978–987

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kahan FM, Kahan JS, Cassidy PJ, Kropp H (1974) The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci 235 (0):364-386

    Google Scholar 

  39. Bouhss A, Crouvoisier M, Blanot D, Mengin-Lecreulx D (2004) Purification and characterization of the bacterial MraY translocase catalyzing the first membrane step of peptidoglycan biosynthesis. J Biol Chem 279(29):29974–29980

    Article  PubMed  CAS  Google Scholar 

  40. Stone KJ, Strominger JL (1971) Mechanism of action of bacitracin: complexation with metal ion and C 55 -isoprenyl pyrophosphate. Proc Natl Acad Sci U S A 68(12):3223–3227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Storm DR, Strominger JL (1973) Complex formation between bacitracin peptides and isoprenyl pyrophosphates. The specificity of lipid-peptide interactions. J Biol Chem 248(11):3940–3945

    Article  PubMed  CAS  Google Scholar 

  42. Schneider T, Gries K, Josten M, Wiedemann I, Pelzer S, Labischinski H, Sahl HG (2009) The lipopeptide antibiotic Friulimicin B inhibits cell wall biosynthesis through complex formation with bactoprenol phosphate. Antimicrob Agents Chemother 53(4):1610–1618

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Hiramatsu K (2001) Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect Dis 1(3):147–155

    Article  PubMed  CAS  Google Scholar 

  44. Cudic P, Kranz JK, Behenna DC, Kruger RG, Tadesse H, Wand AJ, Veklich YI, Weisel JW, McCafferty DG (2002) Complexation of peptidoglycan intermediates by the lipoglycodepsipeptide antibiotic ramoplanin: minimal structural requirements for intermolecular complexation and fibril formation. Proc Natl Acad Sci U S A 99(11):7384–7389

    Google Scholar 

  45. Bierbaum G, Sahl HG (2009) Lantibiotics: mode of action, biosynthesis and bioengineering. Curr Pharm Biotechnol 10:2–18

    Article  PubMed  CAS  Google Scholar 

  46. Sahl HG, Bierbaum G (1998) Lantibiotics: biosynthesis and biological activities of uniquely modified peptides from gram-positive bacteria. Annu Rev Microbiol 52:41–79

    Article  PubMed  CAS  Google Scholar 

  47. Brötz H, Bierbaum G, Leopold K, Reynolds PE, Sahl HG (1998) The lantibiotic mersacidin inhibits peptidoglycan synthesis by targeting lipid II. Antimicrob Agents Chemother 42(1):154–160

    Article  PubMed  PubMed Central  Google Scholar 

  48. Galvez A, Abriouel H, Lopez RL, Ben Omar N (2007) Bacteriocin-based strategies for food biopreservation. Int J Food Microbiol 120(1-2):51–70

    Article  PubMed  CAS  Google Scholar 

  49. Brötz H, Josten M, Wiedemann I, Schneider U, Gotz F, Bierbaum G, Sahl HG (1998) Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics. Mol Microbiol 30(2):317–327

    Article  PubMed  Google Scholar 

  50. Wiedemann I, Breukink E, van Kraaij C, Kuipers OP, Bierbaum G, de Kruijff B, Sahl HG (2001) Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J Biol Chem 276(3):1772–1779

    Article  PubMed  CAS  Google Scholar 

  51. Peschel A, Sahl HG (2006) The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol 4(7):529–536

    Article  PubMed  CAS  Google Scholar 

  52. Sass V, Pag U, Tossi A, Bierbaum G, Sahl HG (2008) Mode of action of human beta-defensin 3 (hBD3) against Staphylococcus aureus and transcriptional analysis of responses to defensin challenge. Int J Med Microbiol 298:619–633

    Article  PubMed  CAS  Google Scholar 

  53. Muthaiyan A, Silverman JA, Jayaswal RK, Wilkinson BJ (2008) Transcriptional profiling reveals that daptomycin induces the Staphylococcus aureus cell wall stress stimulon and genes responsive to membrane depolarization. Antimicrob Agents Chemother 52:980–990

    Article  PubMed  CAS  Google Scholar 

  54. Wecke T, Zuhlke D, Mader U, Jordan S, Voigt B, Pelzer S, Labischinski H, Homuth G, Hecker M, Mascher T (2009) Daptomycin versus Friulimicin B: in-depth profiling of Bacillus subtilis cell envelope stress responses. Antimicrob Agents Chemother 53(4):1619–1623

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Camargo IL, Neoh HM, Cui L, Hiramatsu K (2008) Serial daptomycin selection generates daptomycin-nonsusceptible Staphylococcus aureus strains with a heterogeneous vancomycin-intermediate phenotype. Antimicrob Agents Chemother 52(12):4289–4299

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Kuroda M, Kuroda H, Oshima T, Takeuchi F, Mori H, Hiramatsu K (2003) Two-component system VraSR positively modulates the regulation of cell-wall biosynthesis pathway in Staphylococcus aureus. Mol Microbiol 49(3):807–821

    Article  PubMed  CAS  Google Scholar 

  57. Utaida S, Dunman PM, Macapagal D, Murphy E, Projan SJ, Singh VK, Jayaswal RK, Wilkinson BJ (2003) Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon. Microbiology 149(Pt 10):2719–2732

    Article  PubMed  CAS  Google Scholar 

  58. Sass P, Jansen A, Szekat C, Sass V, Sahl HG, Bierbaum G (2008) The lantibiotic mersacidin is a strong inducer of the cell wall stress response of Staphylococcus aureus. BMC Microbiol 8:186

    Article  PubMed  PubMed Central  Google Scholar 

  59. Müller A, Wenzel M, Strahl H, Grein F, Saaki TNV, Kohl B, Siersma T, Bandow JE, Sahl HG, Schneider T, Hamoen LW (2016) Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proc Natl Acad Sci U S A 113(45):E7077–e7086

    Google Scholar 

  60. Grein F, Müller A, Scherer KM, Liu X, Ludwig KC, Klöckner A, Strach M, Sahl HG, Kubitscheck U, Schneider T (2020) Ca(2+)-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids. Nat Commun 11(1):1455

    Google Scholar 

  61. Cavalleri B, Turconi M, Tamborini G, Occelli E, Cietto G, Pallanza R, Scotti R, Berti M, Romano G, Parenti F (1990) Synthesis and biological activity of some derivatives of rifamycin P. J Med Chem 33(5):1470–1476

    Article  PubMed  CAS  Google Scholar 

  62. Yoshizawa S, Fourmy D, Puglisi JD (1998) Structural origins of gentamicin antibiotic action. EMBO J 17(22):6437–6448

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V (2000) Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407(6802):340–348

    Article  PubMed  CAS  Google Scholar 

  64. Pioletti M, Schlünzen F, Harms J, Zarivach R, Gluhmann M, Avila H, Bashan A, Bartels H, Auerbach T, Jacobi C, Hartsch T, Yonath A, Franceschi F (2001) Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J 20(8):1829–1839

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Schlünzen F, Zarivach R, Harms J, Bashan A, Tocilj A, Albrecht R, Yonath A, Franceschi F (2001) Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413(6858):814–821

    Article  PubMed  Google Scholar 

  66. Long KS, Porse BT (2003) A conserved chloramphenicol binding site at the entrance to the ribosomal peptide exit tunnel. Nucleic Acids Res 31(24):7208–7215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Moazed D, Noller HF (1987) Chloramphenicol, erythromycin, carbomycin and vernamycin B protect overlapping sites in the peptidyl transferase region of 23S ribosomal RNA. Biochimie 69(8):879–884

    Article  PubMed  CAS  Google Scholar 

  68. Cassels R, Oliva B, Knowles D (1995) Occurrence of the regulatory nucleotides ppGpp and pppGpp following induction of the stringent response in staphylococci. J Bacteriol 177(17):5161–5165

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Crosse AM, Greenway DL, England RR (2000) Accumulation of ppGpp and ppGp in Staphylococcus aureus 8325-4 following nutrient starvation. Lett Appl Microbiol 31(4):332–337

    Article  PubMed  CAS  Google Scholar 

  70. Abranches J, Martinez AR, Kajfasz JK, Chavez V, Garsin DA, Lemos JA (2009) The molecular alarmone (p)ppGpp mediates stress responses, vancomycin tolerance, and virulence in Enterococcus faecalis. J Bacteriol 191(7):2248–2256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Reiss S, Pane-Farre J, Fuchs S, Francois P, Liebeke M, Schrenzel J, Lindequist U, Lalk M, Wolz C, Hecker M, Engelmann S (2012) Global analysis of the Staphylococcus aureus response to mupirocin. Antimicrob Agents Chemother 56(2):787–804

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Otaka T, Kaji A (1973) Evidence that fusidic acid inhibits the binding of aminoacyl-tRNA to the donor as well as the acceptor site of the ribosomes. Eur J Biochem 38(1):46–53

    Article  PubMed  CAS  Google Scholar 

  73. Gao YG, Selmer M, Dunham CM, Weixlbaumer A, Kelley AC, Ramakrishnan V (2009) The structure of the ribosome with elongation factor G trapped in the posttranslocational state. Science 326(5953):694–699

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Drlica K, Zhao X (1997) DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev 61(3):377–392

    PubMed  PubMed Central  CAS  Google Scholar 

  75. Reece RJ, Maxwell A (1991) DNA gyrase: structure and function. Crit Rev Biochem Mol Biol 26(3-4):335–375

    Article  PubMed  CAS  Google Scholar 

  76. Roca J (1995) The mechanisms of DNA topoisomerases. Trends Biochem Sci 20(4):156–160

    Article  PubMed  CAS  Google Scholar 

  77. Peng H, Marians KJ (1995) The interaction of Escherichia coli topoisomerase IV with DNA. J Biol Chem 270(42):25286–25290

    Article  PubMed  CAS  Google Scholar 

  78. Danshiitsoodol N, de Pinho CA, Matoba Y, Kumagai T, Sugiyama M (2006) The mitomycin C (MMC)-binding protein from MMC-producing microorganisms protects from the lethal effect of bleomycin: crystallographic analysis to elucidate the binding mode of the antibiotic to the protein. J Mol Biol 360(2):398–408

    Article  PubMed  CAS  Google Scholar 

  79. Claverys JP, Prudhomme M, Martin B (2006) Induction of competence regulons as a general response to stress in gram-positive bacteria. Annu Rev Microbiol 60:451–475

    Article  PubMed  CAS  Google Scholar 

  80. Au N, Kuester-Schoeck E, Mandava V, Bothwell LE, Canny SP, Chachu K, Colavito SA, Fuller SN, Groban ES, Hensley LA, O’Brien TC, Shah A, Tierney JT, Tomm LL, O’Gara TM, Goranov AI, Grossman AD, Lovett CM (2005) Genetic composition of the Bacillus subtilis SOS system. J Bacteriol 187(22):7655–7666

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Friedman N, Vardi S, Ronen M, Alon U, Stavans J (2005) Precise temporal modulation in the response of the SOS DNA repair network in individual bacteria. PLoS Biol 3(7):e238

    Article  PubMed  PubMed Central  Google Scholar 

  82. Kelley WL (2006) Lex marks the spot: the virulent side of SOS and a closer look at the LexA regulon. Mol Microbiol 62(5):1228–1238

    Article  PubMed  CAS  Google Scholar 

  83. Michel B (2005) After 30 years of study, the bacterial SOS response still surprises us. PLoS Biol 3(7):e255

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schaberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517(7535):455–459

    Google Scholar 

  85. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL (2012) Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A 109(29):11663–11668

    Google Scholar 

  86. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Durand-Reville TF, Lahiri S, Thresher J, Livchak S, Gao N, Palmer T, Walkup GK, Fisher SL (2013) Kinetics of avibactam inhibition against Class A, C, and D beta-lactamases. J Biol Chem 288(39):27960–27971

    Google Scholar 

  87. Lahiri SD, Mangani S, Jahic H, Benvenuti M, Durand-Reville TF, De Luca F, Ehmann DE, Rossolini GM, Alm RA, Docquier JD (2015) Molecular basis of selective inhibition and slow reversibility of avibactam against class D carbapenemases: a structure-guided study of OXA-24 and OXA-48. ACS Chem Biol 10(2):591–600

    Google Scholar 

  88. Howe JA, Wang H, Fischmann TO, Balibar CJ, Xiao L, Galgoci AM, Malinverni JC, Mayhood T, Villafania A, Nahvi A, Murgolo N, Barbieri CM, Mann PA, Carr D, Xia E, Zuck P, Riley D, Painter RE, Walker SS, Sherborne B, de Jesus R, Pan W, Plotkin MA, Wu J, Rindgen D, Cummings J, Garlisi CG, Zhang R, Sheth PR, Gill CJ, Tang H, Roemer T (2015) Selective small-molecule inhibition of an RNA structural element. Nature 526(7575):672–677

    Google Scholar 

  89. Imai Y, Meyer KJ, Iinishi A, Favre-Godal Q, Green R, Manuse S, Caboni M, Mori M, Niles S, Ghiglieri M, Honrao C, Ma X, Guo JJ, Makriyannis A, Linares-Otoya L, Böhringer N, Wuisan ZG, Kaur H, Wu R, Mateus A, Typas A, Savitski MM, Espinoza JL, O’Rourke A, Nelson KE, Hiller S, Noinaj N, Schäberle TF, D’Onofrio A, Lewis K (2019) A new antibiotic selectively kills Gram-negative pathogens. Nature 576(7787):459–464

    Google Scholar 

  90. Kaur H, Jakob RP, Marzinek JK, Green R, Imai Y, Bolla JR, Agustoni E, Robinson CV, Bond PJ, Lewis K, Maier T, Hiller S (2021) The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase. Nature 593(7857):125–129

    Google Scholar 

  91. Smith PA, Koehler MFT, Girgis HS, Yan D, Chen Y, Chen Y, Crawford JJ, Durk MR, Higuchi RI, Kang J, Murray J, Paraselli P, Park S, Phung W, Quinn JG, Roberts TC, Rougé L, Schwarz JB, Skippington E, Wai J, Xu M, Yu Z, Zhang H, Tan MW, Heise CE (2018) Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561(7722):189–194

    Google Scholar 

  92. Haydon DJ, Stokes NR, Ure R, Galbraith G, Bennett JM, Brown DR, Baker PJ, Barynin VV, Rice DW, Sedelnikova SE, Heal JR, Sheridan JM, Aiwale ST, Chauhan PK, Srivastava A, Taneja A, Collins I, Errington J, Czaplewski LG (2008) An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321(5896):1673–1675

    Article  PubMed  CAS  Google Scholar 

  93. Haydon DJ, Bennett JM, Brown D, Collins I, Galbraith G, Lancett P, Macdonald R, Stokes NR, Chauhan PK, Sutariya JK, Nayal N, Srivastava A, Beanland J, Hall R, Henstock V, Noula C, Rockley C, Czaplewski L (2010) Creating an antibacterial with in vivo efficacy: synthesis and characterization of potent inhibitors of the bacterial cell division protein FtsZ with improved pharmaceutical properties. J Med Chem 53(10):3927–3936

    Google Scholar 

  94. Adams DW, Errington J (2009) Bacterial cell division: assembly, maintenance and disassembly of the Z ring. Nat Rev Microbiol 7(9):642–653

    Article  PubMed  CAS  Google Scholar 

  95. Tan CM, Therien AG, Lu J, Lee SH, Caron A, Gill CJ, Lebeau-Jacob C, Benton-Perdomo L, Monteiro JM, Pereira PM, Elsen NL, Wu J, Deschamps K, Petcu M, Wong S, Daigneault E, Kramer S, Liang L, Maxwell E, Claveau D, Vaillancourt J, Skorey K, Tam J, Wang H, Meredith TC, Sillaots S, Wang-Jarantow L, Ramtohul Y, Langlois E, Landry F, Reid JC, Parthasarathy G, Sharma S, Baryshnikova A, Lumb KJ, Pinho MG, Soisson SM, Roemer T (2012) Restoring methicillin-resistant Staphylococcus aureus susceptibility to beta-lactam antibiotics. Sci Transl Med 4(126):126ra135

    Google Scholar 

  96. Adams DW, Wu LJ, Czaplewski LG, Errington J (2011) Multiple effects of benzamide antibiotics on FtsZ function. Mol Microbiol 80(1):68–84

    Article  PubMed  CAS  Google Scholar 

  97. Andreu JM, Schaffner-Barbero C, Huecas S, Alonso D, Lopez-Rodriguez ML, Ruiz-Avila LB, Nunez-Ramirez R, Llorca O, Martin-Galiano AJ (2010) The antibacterial cell division inhibitor PC190723 is an FtsZ polymer-stabilizing agent that induces filament assembly and condensation. J Biol Chem 285(19):14239–14246

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Elsen NL, Lu J, Parthasarathy G, Reid JC, Sharma S, Soisson SM, Lumb KJ (2012) Mechanism of action of the cell-division inhibitor PC190723: modulation of FtsZ assembly cooperativity. J Am Chem Soc 134(30):12342–12345

    Google Scholar 

  99. Anderson DE, Kim MB, Moore JT, O’Brien TE, Sorto NA, Grove CI, Lackner LL, Ames JB, Shaw JT (2012) Comparison of small molecule inhibitors of the bacterial cell division protein FtsZ and identification of a reliable cross-species inhibitor. ACS Chem Biol 7(11):1918–1928

    Google Scholar 

  100. Matsui T, Yamane J, Mogi N, Yamaguchi H, Takemoto H, Yao M, Tanaka I (2012) Structural reorganization of the bacterial cell-division protein FtsZ from Staphylococcus aureus. Acta Crystallogr Sect D Biol Crystallogr 68(Pt 9):1175–1188

    Google Scholar 

  101. Brötz-Oesterhelt H, Beyer D, Kroll HP, Endermann R, Ladel C, Schroeder W, Hinzen B, Raddatz S, Paulsen H, Henninger K, Bandow JE, Sahl HG, Labischinski H (2005) Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat Med 11(10):1082–1087

    Article  PubMed  Google Scholar 

  102. Michel KH, Kastner RE (1985) A54556 antibiotics and process for production thereof. US patent 4,492,650, 1985

    Google Scholar 

  103. 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 Mol Med 1(1):37–49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Lee BG, Park EY, Jeon H, Sung KH, Paulsen H, Rübsamen-Schaeff H, Brötz-Oesterhelt H, Song HK (2010) Structures of ClpP in complex with a novel class of antibiotics reveal its activation mechanism. Nat Struct Mol Biol 17(4):471–478

    Article  PubMed  CAS  Google Scholar 

  105. Gersch M, Famulla K, Dahmen M, Gobl C, Malik I, Richter K, Korotkov VS, Sass P, Rubsamen-Schaeff H, Madl T, Brotz-Oesterhelt H, Sieber SA (2015) AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control. Nat Commun 6:6320

    Google Scholar 

  106. Pan S, Malik IT, Thomy D, Henrichfreise B, Sass P (2019) The functional ClpXP protease of Chlamydia trachomatis requires distinct clpP genes from separate genetic loci. Sci Rep 9(1):14129

    Google Scholar 

  107. Sass P, Brötz-Oesterhelt H (2013) Bacterial caseinolytic proteases as novel targets for antibacterial treatment. Int J Med Microbiol 304:23

    PubMed  Google Scholar 

  108. Baker TA, Sauer RT (2012) ClpXP, an ATP-powered unfolding and protein-degradation machine. Biochim Biophys Acta 1823(1):15–28

    Google Scholar 

  109. Li DH, Chung YS, Gloyd M, Joseph E, Ghirlando R, Wright GD, Cheng YQ, Maurizi MR, Guarne A, Ortega J (2010) Acyldepsipeptide antibiotics induce the formation of a structured axial channel in ClpP: a model for the ClpX/ClpA-bound state of ClpP. Chem Biol 17(9):959–969

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Sass P, Josten M, Famulla K, Schiffer G, Sahl HG, Hamoen L, Brötz-Oesterhelt H (2011) Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc Natl Acad Sci USA 108(42):17474–17479

    Google Scholar 

  111. Silber N, Mayer C, Matos C, Sass P (2021) Progression of the late-stage divisome is unaffected by the depletion of the cytoplasmic FtsZ pool. Commun Biol 4(1):270

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Mayer C, Sass P, Brötz-Oesterhelt H (2019) Consequences of dosing and timing on the antibacterial effects of ADEP antibiotics. Int J Med Microbiol 309(7):151329

    Google Scholar 

  113. Silber N, Matos C, Mayer C, Sass P (2020) Cell division protein FtsZ: from structure and mechanism to antibiotic target. Future Microbiol 15:801–831

    Article  PubMed  CAS  Google Scholar 

  114. Silber N, Pan S, Schäkermann S, Mayer C, Brötz-Oesterhelt H, Sass P (2020) Cell division protein FtsZ is unfolded for N-terminal degradation by antibiotic-activated ClpP. MBio 11(3):e01006–e01020

    Article  PubMed  PubMed Central  Google Scholar 

  115. Famulla K, Sass P, Malik I, Akopian T, Kandror O, Alber M, Hinzen B, Ruebsamen-Schaeff H, Kalscheuer R, Goldberg AL, Brotz-Oesterhelt H (2016) Acyldepsipeptide antibiotics kill mycobacteria by preventing the physiological functions of the ClpP1P2 protease. Mol Microbiol. 101(2):194-209

    Google Scholar 

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Acknowledgment

I appreciate funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): Project-ID 398967434 (TRR 261-A02), the German Center for Infection Research (DZIF; TTU 09.815), as well as support by infrastructural funding from the Cluster of Excellence EXC 2124 Controlling Microbes to Fight Infections. I deeply thank Anne Berscheid for her continuous support, helpful discussions, and endless patience.

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  1. Interfaculty Institute for Microbiology and Infection Medicine, Microbial Bioactive Compounds, University of Tübingen, Tübingen, Germany

    Peter Sass

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    Peter Sass

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Sass, P. (2023). Antibiotics: Precious Goods in Changing Times. In: Sass, P. (eds) Antibiotics. Methods in Molecular Biology, vol 2601. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2855-3_1

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  • DOI: https://doi.org/10.1007/978-1-0716-2855-3_1

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