Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Possible drugs for the treatment of bacterial infections in the future: anti-virulence drugs

The Journal of Antibiotics volume 74, pages 24–41 (2021)Cite this article

Subjects

Abstract

Antibiotic resistance is a global threat that should be urgently resolved. Finding a new antibiotic is one way, whereas the repression of the dissemination of virulent pathogenic bacteria is another. From this point of view, this paper summarizes first the mechanisms of conjugation and transformation, two important processes of horizontal gene transfer, and then discusses the approaches for disarming virulent pathogenic bacteria, that is, virulence factor inhibitors. In contrast to antibiotics, anti-virulence drugs do not impose a high selective pressure on a bacterial population, and repress the dissemination of antibiotic resistance and virulence genes. Disarmed virulence factors make virulent pathogens avirulent bacteria or pathobionts, so that we human will be able to coexist with these disarmed bacteria peacefully.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Fleming A. On the antibacterial action of cultures of penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol. 1929;10:226–36.

    CAS  PubMed Central  Google Scholar 

  2. Chain E, Florey HW, Gardner AD, Heatley NG, Jennings MA, Orr-Ewing J, Sanders AG. Penicillin as a chemotherapeutic agent. Lancet. 1940;236:226–8.

    Google Scholar 

  3. Abraham EP, Chain E, Fletcher CM, Florey HW, Gardner AD, Heatley NG, Jennings MA. Further observations on penicillin. Lancet. 1941;238:177–89.

    Google Scholar 

  4. Abraham EP, Chain E, Fletcher CM, Florey HW, Gardner AD, Heatley NG, Jennings MA. Further observation on penicillin. Eur J Clin Pharmacol 1992;42:3–9.

    CAS  PubMed  Google Scholar 

  5. Pongdee T, Li JT. Evaluation and management of penicillin allergy. Mayo Clin Proc. 2018;93:101–7.

    CAS  PubMed  Google Scholar 

  6. Silver LL. Challenges of antibacterial discovery. Clin Microbiol Rev. 2011;24:71–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lewis K. Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013;12:371–87.

    CAS  PubMed  Google Scholar 

  8. Walsh CT, Wencewicz TA. Prospects for new antibiotics: a molecule-centered perspective. J Antibiot. 2014;67:7–22.

    CAS  Google Scholar 

  9. Katz L, Baltz RH. Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol. 2016;43:155–76. 2016

    CAS  PubMed  Google Scholar 

  10. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6:29–40.

    CAS  PubMed  Google Scholar 

  11. Bentley SD, Chater KF, Cerdeno-Tarragam AM, Challis GL, Thomson NR, et al. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature. 2002;417:141–7.

    PubMed  Google Scholar 

  12. Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, et al. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol. 2003;21:526–31.

    PubMed  Google Scholar 

  13. Ohnishi Y, Ishikawa J, Hara H, Suzuki H, Ikenoya M, et al. Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol. 2008;190:4050–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Orth JD, Conrad TM, Na J, Lerman JA, Nam H, et al. A comprehensive genome-scale reconstruction of Escherichia coli metabolism-2011. Mol Syst Biol. 2011;7:535. https://doi.org/10.1038/msb.2011.65

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bosi E, Monk JM, Aziz RK, Fondi M, Nizet V, Palsson BØ. Comparative genome-scale modelling of Staphylococcus aureus strains identifies strain-specific metabolic capabilities linked to pathogenicity. Proc Natl Acad Sci USA. 2016;113:E3801–3809.

    CAS  PubMed  Google Scholar 

  16. Stover CK, Pham XQ, Erwin AL, Mizoguchi SD, Warrener P, et al. Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen. Nature. 2000;406:959–64.

    CAS  PubMed  Google Scholar 

  17. Bachmann BO, Van Lanen SG, Baltz RH. Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? J Ind Microbiol Biotechnol. 2014;41:175–84.

    CAS  PubMed  Google Scholar 

  18. Nett M, Ikeda H, Moore BS. Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep. 2009;26:1362–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Shimizu Y, Ogata H, Goto S. Type III polyketide synthases: functional classification and phylogenomics. Chembiochem. 2017;18:50–65.

    CAS  PubMed  Google Scholar 

  20. Clardy J, Fischbach MA, Walsh CT. New antibiotics from bacterial natural products. Nat Biotechnol. 2006;24:1541–50.

    CAS  PubMed  Google Scholar 

  21. Lewis K, Epstein S, D’Onofrio A, Ling LL. Uncultured microorganisms as a source of secondary metabolites. J Antibiot. 2010;63:468–76.

    CAS  Google Scholar 

  22. Colameco S, Elliot MA. Non-coding RNAs as antibiotic targets. Biochem Pharm. 2017;133:29–42.

    CAS  PubMed  Google Scholar 

  23. Culp E, Wright GD. Bacterial proteases, untapped antimicrobial drug targets. J Antibiot. 2017;70:366–77.

    CAS  Google Scholar 

  24. Erwin AL. Antibacterial drug discovery targeting the lipopolysaccharide biosynthetic enzyme LpxC. Cold Spring Harb Perspect Med. 6;2016. https://doi.org/10.1101/cshperspect.a025304

  25. Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;325:1089–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Demain AL, Gomez-Ortiz B, Ruiz-Villafan B, Rodriguez-Sanoja R, Sanchez S. Recent findings of molecules with anti-infective activity: screening of non-conventional sources. Curr Opin Pharm. 2019;48:40–47.

    CAS  Google Scholar 

  27. Diez J, Martinez JP, Mestres J, Sasse F, Frank R, Meyerhans A. Myxobacteria: natural pharmaceutical factories. Microb Cell Fact. 2012;11:52. https://doi.org/10.1186/1475-2859-11-52

    Article  PubMed  PubMed Central  Google Scholar 

  28. Landwehr W, Wolf C, Wink J. Actinobacteria and myxobacteria-two of the most important bacterial resources for novel antibiotics. Curr Top Microbiol Immunol. 2016;398:273–302.

    CAS  PubMed  Google Scholar 

  29. Wilson MR, Zha L, Balskus EP. Natural product discovery from the human microbiome. J Biol Chem. 2017;292:8546–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Donia MS, Cimermancic P, Schulze CJ, Wieland Brown LC, Martin J, Mitreva M, et al. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell. 2014;158:1402–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Dingsdag SA, Hunter N. Metronidazole: an update on metabolism, structure-cytotoxicity and resistance mechanisms. J Antimicrob Chemother. 2018;73:265–79.

    CAS  PubMed  Google Scholar 

  32. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015;13:42–51.

    CAS  PubMed  Google Scholar 

  33. Ogawara H. Comparison of antibiotic resistance mechanisms in antibiotic-producing and pathogenic bacteria. Molecules. 2019;24:3430. https://doi.org/10.3390/molecules24193430

    Article  CAS  PubMed Central  Google Scholar 

  34. Lerminiaux NA, Cameron ADS. Horizontal transfer of antibiotic resistance genes in clinical environments. Can J Microbiol. 2019;65:34–44.

    CAS  PubMed  Google Scholar 

  35. D’Costa VM, McGrann KM, Hughes DW, Wright GD. Sampling the antibiotic resistome. Science. 2006;311:374–7.

    PubMed  Google Scholar 

  36. Nesme J, Simonet P. The soil resistome: a critical review on antibiotic resistance origins, ecology and dissemination potential in telluric bacteria. Environ Microbiol. 2015;17:913–30.

    PubMed  Google Scholar 

  37. Crofts TS, Gasparrini AJ, Dantas G. Next-generation approaches to understand and combat the antibiotic resistome. Nat Rev Microbiol. 2017;15:422–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Munck C, Hashim Ellabaan MM, Klausen MS, Sommer MOA. The resistome of common human pathogens. bioRxiv. 2017. Preprint at https://doi.org/10.1101/140194

  39. Cox G, Wright GD. Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int J Med Microbiol. 2013;303:287–92.

    CAS  PubMed  Google Scholar 

  40. Olivares J, Bernardini A, Garcia-Leon G, Corona F, Sanchez MB, Martinez JL. The intrinsic resistome of bacterial pathogens. Front Microbiol. 2013;4:103.

    PubMed  PubMed Central  Google Scholar 

  41. Culyba MJ, Mo CY, Kohli RM. Targets for combating the evolution of acquired antibiotic resistance. Biochemistry. 2015;54:3573–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sandoval-Motta S, Aldana M. Adaptive resistance to antibiotics in bacteria: a systems biology perspective. Wiley Interdiscip Rev Syst Biol Med. 2016;8:253–67.

    PubMed  Google Scholar 

  43. Martinez JL. Ecology and evolution of chromosomal gene transfer between environmental microorganisms and pathogens. Microbiol Spectr. 6;2018. https://doi.org/10.1128/microbiolspec.MTBP-0006-2016

  44. Peterson E, Kaur P. Antibiotic resistance mechanisms in bacteria: relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens. Front Microbiol. 2018;9:2928. https://doi.org/10.3389/fmicb.2018.02928

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bengtsson-Palme J, Kristiansson E, Larsson DGJ. Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiol Rev. 2018;42:69–80.

    Google Scholar 

  46. Perry J, Waglechner N, Wright G. The prehistory of antibiotic resistance. Cold Spring Harb Perspect Med. 2016;6:a025197. pii

    PubMed  PubMed Central  Google Scholar 

  47. Karkman A, Do TT, Walsh F, Virta MPJ. Antibiotic-resistance genes in waste water. Trends Microbiol. 2018;26:220–8.

    CAS  PubMed  Google Scholar 

  48. Knoppel A, Nasvall J, Andersson DI. Evolution of antibiotic resistance without antibiotic exposure. Antimicrob Agents Chemother. 2017;61:e01495–17.

    PubMed  PubMed Central  Google Scholar 

  49. Wistrand-Yuen E, Knopp M, Hjort K, Koskiniemi S, Berg OG, Andersson DI. Evolution of high-level resistance during low-level antibiotic exposure. Nat Commun. 2018;9:1599.

    PubMed  PubMed Central  Google Scholar 

  50. Torres-Barcelo C. The disparate effects of bacteriophages on antibiotic-resistant bacteria. Emerg Microbes Infect. 2018;7:168. https://doi.org/10.1038/s41426-018-0169-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Grohmann E, Christie PJ, Waksman G, Backert S. Type IV secretion in Gram-negative and Gram-positive bacteria. Mol Microbiol. 2018;107:455–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang W, Rong C, Chen C, Gao GF. Type-IVC secretion system: a novel subclass of type IV secretion system (T4SS) common existing in gram-positive genus Streptococcus. PLoS ONE. 2012;7:e46390.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Price VJ, McBride SW, Hullahalli K, Chatterjee A, Duerkop BA, Palmer KL. Enterococcus faecalis CRISPR-Cas is a robust barrier to conjugative antibiotic resistance dissemination in the murine intestine. mSphere. 2019;4:e00464–19. https://doi.org/10.1128/mSphere.00464-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hirt H, Manias DA, Bryan EM, Klein JR, Marklund JK, Staddon JH, et al. Characterization of the pheromone response of the Enterococcus faecalis conjugative plasmid pCF10: complete sequence and comparative analysis of the transcriptional and phenotypic responses of pCF10-containing cells to pheromone induction. J Bacteriol. 2005;187:1044–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bae T, Kozlowicz B, Dunny GM. Two targets in pCF10 DNA for PrgX binding: their role in production of Qa and prgX mRNA and in regulation of pheromone-inducible conjugation. J Mol Biol. 2002;315:995–1007.

    CAS  PubMed  Google Scholar 

  56. Shi K, Brown CK, Gu ZY, Kozlowicz BK, Dunny GM, Ohlendorf DH, Earhart CA. Structure of peptide sex pheromone receptor PrgX and PrgX/pheromone complexes and regulation of conjugation in Enterococcus faecalis. Proc Natl Acad Sci USA. 2005;102:18596–601.

    CAS  PubMed  Google Scholar 

  57. Antiporta MH, Dunny GM. ccfA, the genetic determinant for the cCF10 peptide pheromone in Enterococcus faecalis OG1RF. J Bacteriol. 2002;184:1155–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Berntsson RP, Schuurman-Wolters GK, Dunny G, Slotboom DJ, Poolman B. Structure and mode of peptide binding of pheromone receptor PrgZ. J Biol Chem. 2012;287:37165–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kohler V, Keller W, Grohmann E. Regulation of Gram-positive conjugation. Front Microbiol. 2019;10:1134. https://doi.org/10.3389/fmicb.2019.01134

    Article  PubMed  PubMed Central  Google Scholar 

  60. Chatterjee A, Cook LC, Shu CC, Chen Y, Manias DA, et al. Antagonistic self-sensing and mate-sensing signaling controls antibiotic-resistance transfer. Proc Natl Acad Sci USA. 2013;110:7086–90.

    CAS  PubMed  Google Scholar 

  61. Alcoforado Diniz J, Liu YC, Coulthurst SJ. Molecular weaponry: diverse effectors delivered by the Type VI secretion system. Cell Microbiol. 2015;17:1742–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Terradot L, Berge C, Waksman G. Structural and molecular biology of type IV secretion systems. Curr Top Microbiol Immunol. 2017;413:31–60.

    PubMed  Google Scholar 

  63. Christie PJ. The mosaic type IV secretion systems. EcoSal Plus. 7;2016. https://doi.org/10.1128/ecosalplus.ESP-0020-2015

  64. Whitaker N, Chen Y, Jakubowski SJ, Sarkar MK, Li F, Christie PJ. The all-alpha domains of coupling proteins from the Agrobacterium tumefaciens VirB/VirD4 and Enterococcus faecalis pCF10-encoded type IV secretion systems confer specificity to binding of cognate DNA substrates. J Bacteriol. 2015;197:2335–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen Y, Staddon JH, Dunny GM. Specificity determinants of conjugative DNA processing in the Enterococcus faecalis plasmid pCF10 and the Lactococcus lactis plasmid pRS01. Mol Microbiol. 2007;63:1549–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Christie PJ, Whitaker N, Gonzalez-Rivera C. Mechanism and structure of the bacterial type IV secretion systems. Biochim Biophys Acta. 2014;1843:1578–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Lawley TD, Klimke WA, Gubbins MJ, Frost LS. F factor conjugation is a true type IV secretion system. FEMS Microbiol Lett. 2003;224:1–15.

    CAS  PubMed  Google Scholar 

  68. Waksman G. From conjugation to T4S systems in Gram-negative bacteria: a mechanistic biology perspective. EMBO Rep. 2019;20:e47012. https://doi.org/10.15252/embr.201847012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Low HH, Gubellini F, Rivera-Calzada A, Braun N, Connery S, et al. Structure of a type IV secretion system. Nature. 2014;508:550–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Redzej A, Ukleja M, Connery S, Trokter M, Felisberto-Rodrigues C, et al. Structure of a VirD4 coupling protein bound to a VirB type IV secretion machinery. EMBO J. 2017;36:3080–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Johnston C, Martin B, Fichant G, Polard P, Claverys JP. Bacterial transformation: distribution, shared mechanisms and divergent control. Nat Rev Microbiol. 2014;12:181–96.

    CAS  PubMed  Google Scholar 

  72. Johnsborg O, Eldholm V, Havarstein LS. Natural genetic transformation: prevalence, mechanisms and function. Res Microbiol. 2007;158:767–78.

    CAS  PubMed  Google Scholar 

  73. Hofreuter D, Odenbreit S, Haas R. Natural transformation competence in Helicobacter pylori is mediated by the basic components of a type IV secretion system. Mol Microbiol. 2001;41:379–91.

    CAS  PubMed  Google Scholar 

  74. Balaban M, Battig P, Muschiol S, Tirier SM, Wartha F, Normark S, Henriques-Normark B. Secretion of a pneumococcal type II secretion system pilus correlates with DNA uptake during transformation. Proc Natl Acad Sci USA. 2014;111:E758–65.

    CAS  PubMed  Google Scholar 

  75. Ellison CK, Dalia TN, Vidal Ceballos A, Wang JC, Biais N, Brun YV, Dalia AB. Retraction of DNA-bound type IV competence pili initiates DNA uptake during natural transformation in Vibrio cholerae. Nat Microbiol. 2018;3:773–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Laurenceau R, Pehau-Arnaudet G, Baconnais S, Gault J, Malosse C, Dujeancourt A, et al. A type IV pilus mediates DNA binding during natural transformation in Streptococcus pneumoniae. PLoS Pathog. 2013;9:e1003473. https://doi.org/10.1371/journal.ppat.1003473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen I, Provvedi R, Dubnau D. A macromolecular complex formed by a pilin-like protein in competent Bacillus subtilis. J Biol Chem. 2006;281:21720–7.

    CAS  PubMed  Google Scholar 

  78. Varga JJ, Nguyen V, O’Brien DK, Rodgers K, Walker RA, Melville SB. Type IV pili-dependent gliding motility in the Gram-positive pathogen Clostridium perfringens and other Clostridia. Mol Microbiol. 2006;62:680–94.

    CAS  PubMed  Google Scholar 

  79. Tammam S, Sampaleanu LM, Koo J, Manoharan K, Daubaras M, et al. PilMNOPQ from the Pseudomonas aeruginosa type IV pilus system form a transenvelope protein interaction network that interacts with PilA. J Bacteriol. 2013;195:2126–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Winther-Larsen HC, Wolfgang M, Dunham S, van Putten JP, Dorward D, Lovold C, et al. A conserved set of pilin-like molecules controls type IV pilus dynamics and organelle-associated functions in Neisseria gonorrhoeae. Mol Microbiol. 2005;56:903–17.

    CAS  PubMed  Google Scholar 

  81. Lee MS, Morrison DA. Identification of a new regulator in Streptococcus pneumoniae linking quorum sensing to competence for genetic transformation. J Bacteriol. 1999;181:5004–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Turgay K, Hahn J, Burghoorn J, Dubnau D. Competence in Bacillus subtilis is controlled by regulated proteolysis of a transcription factor. EMBO J. 1998;17:6730–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Higgins DA, Pomianek ME, Kraml CM, Taylor RK, et al. The major Vibrio cholerae autoinducer and its role in virulence factor production. Nature. 2007;450:883–6.

    CAS  PubMed  Google Scholar 

  84. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol. 2010;8:260–71.

    CAS  PubMed  Google Scholar 

  85. Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science. 2006;312:1944–6.

    CAS  PubMed  Google Scholar 

  86. Casadevall A, Pirofski LA. Host-pathogen interactions: redefining the basic concepts of virulence and pathogenicity. Infect Immun. 1999;67:3703–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Wu HJ, Wang AH, Jennings MP. Discovery of virulence factors of pathogenic bacteria. Curr Opin Chem Biol. 2008;12:93–101.

    CAS  PubMed  Google Scholar 

  88. Maura D, Ballok AE, Rahme LG. Considerations and caveats in anti-virulence drug development. Curr Opin Microbiol. 2016;33:41–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ruer S, Pinotsis N, Steadman D, Waksman G, Remaut H. Virulence-targeted antibacterials: concept, promise, and susceptibility to resistance mechanisms. Chem Biol Drug Des. 2015;86:379–99.

    CAS  PubMed  Google Scholar 

  90. Vasu K, Nagaraja V. Diverse functions of restriction-modification systems in addition to cellular defense. Microbiol Mol Biol Rev. 2013;77:53–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Maji B, Gangopadhyay SA, Lee M, Shi M, Wu P, Heler R, et al. A high-throughput platform to identify small-molecule inhibitors of CRISPR-Cas9. Cell. 2019;177:1067–79.e19.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Dupuis ME, Villion M, Magadan AH, Moineau S. CRISPR-Cas and restriction-modification systems are compatible and increase phage resistance. Nat Commun. 2013;4:2087. https://doi.org/10.1038/ncomms3087

    Article  CAS  PubMed  Google Scholar 

  93. Swarts DC, Jore MM, Westra ER, Zhu Y, Janssen JH, Snijders AP, et al. DNA-guided DNA interference by a prokaryotic Argonaute. Nature. 2014;507:258–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Boudaher E, Shaffer CL. Inhibiting bacterial secretion systems in the fight against antibiotic resistance. Medchemcomm. 2019;10:682–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Cabezon E, de la Cruz F, Arechaga I. Conjugation inhibitors and their potential use to prevent dissemination of antibiotic resistance genes in bacteria. Front Microbiol. 2017;8:2329.

    PubMed  PubMed Central  Google Scholar 

  96. Garcillan-Barcia MP, Jurado P, Gonzalez-Perez B, Moncalian G, Fernandez LA, de la Cruz F. Conjugative transfer can be inhibited by blocking relaxase activity within recipient cells with intrabodies. Mol Microbiol. 2007;63:404–16.

    CAS  PubMed  Google Scholar 

  97. Lujan SA, Guogas LM, Ragonese H, Matson SW, Redinbo MR. Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase. Proc Natl Acad Sci USA. 2007;104:12282–7.

    CAS  PubMed  Google Scholar 

  98. Nash RP, McNamara DE, Ballentine WK III, Matson SW, Redinbo MR. Investigating the impact of bisphosphonates and structurally related compounds on bacteria containing conjugative plasmids. Biochem Biophys Res Commun. 2012;424:697–703.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ojala V, Laitalainen J, Jalasvuori M. Fight evolution with evolution: plasmid-dependent phages with a wide host range prevent the spread of antibiotic resistance. Evol Appl. 2013;6:925–32.

    PubMed  PubMed Central  Google Scholar 

  100. Hagens S, Habel A, Blasi U. Augmentation of the antimicrobial efficacy of antibiotics by filamentous phage. Microb Drug Resist. 2006;12:164–8.

    CAS  PubMed  Google Scholar 

  101. Knolle P. Evidence for the identity of the mating-specific site of male cells of Escherichia coli with the receptor site of an RNA phage. Biochem Biophys Res Commun. 1967;27:81–87.

    CAS  PubMed  Google Scholar 

  102. Lin A, Jimenez J, Derr J, Vera P, Manapat ML, Esvelt KM, Villanueva L, Liu DR, Chen IA. Inhibition of bacterial conjugation by phage M13 and its protein g3p: quantitative analysis and model. PLoS ONE. 2011;6:e19991. https://doi.org/10.1371/journal.pone.0019991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. May T, Tsuruta K, Okabe S. Exposure of conjugative plasmid carrying Escherichia coli biofilms to male-specific bacteriophages. ISME J. 2011;5:771–5.

    CAS  PubMed  Google Scholar 

  104. Pinkner JS, Remaut H, Buelens F, Miller E, Aberg V, Pemberton N, et al. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci USA. 2006;103:17897–902.

    CAS  PubMed  Google Scholar 

  105. Lopez D, Vlamakis H, Kolter R. Biofilms. Cold Spring Harb Perspect Biol. 2010;2:a000398.

    PubMed  PubMed Central  Google Scholar 

  106. Shakhnovich EA, Hung DT, Pierson E, Lee K, Mekalanos JJ. Virstatin inhibits dimerization of the transcriptional activator ToxT. Proc Natl Acad Sci USA. 2007;104:2372–7.

    CAS  PubMed  Google Scholar 

  107. Aberg V, Almqvist F. Pilicides-small molecules targeting bacterial virulence. Org Biomol Chem. 2007;5:1827–34.

    PubMed  Google Scholar 

  108. Chahales P, Hoffman PS, Thanassi DG. Nitazoxanide inhibits pilus biogenesis by interfering with folding of the usher protein in the outer membrane. Antimicrob Agents Chemother. 2016;60:2028–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bouckaert J, Berglund J, Schembri M, De Genst E, Cools L, Wuhrer M. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Mol Microbiol. 2005;55:441–55.

    CAS  PubMed  Google Scholar 

  110. Jacobitz AW, Kattke MD, Wereszczynski J, Clubb RT. Sortase transpeptidases: structural biology and catalytic mechanism. Adv Protein Chem Struct Biol. 2017;109:223–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Green ER, Mecsas J. Bacterial secretion systems: an overview. Microbiol Spectr. 4;2016. https://doi.org/10.1128/microbiolspec.VMBF-0012-2015

  112. Liu B, Chen F, Bi C, Wang L, Zhong X, Cai H, et al. Quercitrin, an inhibitor of sortase A, interferes with the adhesion of Staphylococcal aureus. Molecules. 2015;20:6533–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Suree N, Yi SW, Thieu W, Marohn M, Damoiseaux R, Chan A, et al. Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors. Bioorg Med Chem. 2009;17:7174–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Oganesyan V, Peng L, Damschroder MM, Cheng L, Sadowska A, Tkaczyk C, et al. Mechanisms of neutralization of a human anti-α-toxin antibody. J Biol Chem. 2014;289:29874–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang-Lin SX, Balthasar JP. Pharmacokinetic and pharmacodynamic considerations for the use of monoclonal antibodies in the treatment of bacterial infections. Antibodies. 2018;7:E5. https://doi.org/10.3390/antib7010005

    Article  CAS  PubMed  Google Scholar 

  116. Sauter KA, Melton-Celsa AR, Larkin K, Troxell ML, O’Brien AD, Magun BE. Mouse model of hemolytic-uremic syndrome caused by endotoxin-free Shiga toxin 2 (Stx2) and protection from lethal outcome by anti-Stx2 antibody. Infect Immun. 2008;76:4469–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kisiela DI, Avagyan H, Friend D, Jalan A, Gupta S, Interlandi G, et al. Inhibition and reversal of microbial attachment by an antibody with parasteric activity against the FimH adhesin of uropathogenic E. coli. PLoS Pathog. 2015;11:e1004857.

    PubMed  PubMed Central  Google Scholar 

  118. Fernandez-Lopez R, Machon C, Longshaw CM, Martin S, Molin S, Zechner EL, et al. Unsaturated fatty acids are inhibitors of bacterial conjugation. Microbiology. 2005;151:3517–26.

    CAS  PubMed  Google Scholar 

  119. Getino M, Sanabria-Rios DJ, Fernandez-Lopez R, Campos-Gomez J, Sanchez-Lopez JM, Fernandez A, et al. Synthetic fatty acids prevent plasmid-mediated horizontal gene transfer. mBio. 2015;6:e01032–15. https://doi.org/10.1128/mBio.01032-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ripoll-Rozada J, Garcia-Cazorla Y, Getino M, Machon C, Sanabria-Rios D, de la Cruz F, et al. Type IV traffic ATPase TrwD as molecular target to inhibit bacterial conjugation. Mol Microbiol. 2016;100:912–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Garcia-Cazorla Y, Getino M, Sanabria-Rios DJ, Carballeira NM, de la Cruz F, Arechaga I, Cabezon E. Conjugation inhibitors compete with palmitic acid for binding to the conjugative traffic ATPase TrwD, providing a mechanism to inhibit bacterial conjugation. J Biol Chem. 2018;293:16923–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Getino M, Fernandez-Lopez R, Palencia-Gandara C, Campos-Gomez J, Sanchez-Lopez JM, Martinez M, et al. Tanzawaic acids, a chemically novel set of bacterial conjugation inhibitors. PLoS ONE. 2016;11:e0148098. https://doi.org/10.1371/journal.pone.0148098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hilleringmann M, Pansegrau W, Doyle M, Kaufman S, MacKichan ML, Gianfaldoni C, et al. Inhibitors of Helicobacter pylori ATPase Cagα block CagA transport and cag virulence. Microbiology. 2006;152:2919–30.

    CAS  PubMed  Google Scholar 

  124. Sayer JR, Wallden K, Pesnot T, Campbell F, Gane PJ, Simone M, et al. 2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion. Bioorg Med Chem. 2014;22:6459–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Shaffer CL, Good JA, Kumar S, Krishnan KS, Gaddy JA, Loh JT, et al. Peptidomimetic small molecules disrupt type IV secretion system activity in diverse bacterial pathogens. mBio. 2016;7:e00221–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Swietnicki W, Carmany D, Retford M, Guelta M, Dorsey R, Bozue J, et al. Identification of small-molecule inhibitors of Yersinia pestis type III secretion system YscN ATPase. PLoS One. 2011;6:e19716. https://doi.org/10.1371/journal.pone.0019716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Case HB, Mattock DS, Dickenson NE. Shutting down Shigella secretion: characterizing small molecule type three secretion system ATPase inhibitors. Biochemistry. 2018;57:6906–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Paschos A, den Hartigh A, Smith MA, Atluri VL, Sivanesan D, Tsolis RM, Baron C. An in vivo high-throughput screening approach targeting the type IV secretion system component VirB8 identified inhibitors of Brucella abortus 2308 proliferation. Infect Immun. 2011;79:1033–43.

    CAS  PubMed  Google Scholar 

  129. Casu B, Smart J, Hancock MA, Smith M, Sygusch J, Baron C. Structural analysis and inhibition of TraE from the pKM101 Type IV secretion system. J Biol Chem. 2016;291:23817–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Galan JE, Waksman G. Protein-injection machines in bacteria. Cell. 2018;172:1306–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Hachani A, Wood TE, Filloux A. Type VI secretion and anti-host effectors. Curr Opin Microbiol. 2016;29:81–93.

    CAS  PubMed  Google Scholar 

  132. Chatterjee S, Chaudhury S, McShan AC, Kaur K, De Guzman RN. Structure and biophysics of type III secretion in bacteria. Biochemistry. 2013;52:2508–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Notti RQ, Stebbins CE. The structure and function of type III secretion systems. Microbiol Spectr. 4;2016. https://doi.org/10.1128/microbiolspec.VMBF-0004-2015

  134. Kauppi AM, Nordfelth R, Uvell H, Wolf-Watz H, Elofsson M. Targeting bacterial virulence: inhibitors of type III secretion in Yersinia. Chem Biol. 2003;10:241–9.

    CAS  PubMed  Google Scholar 

  135. Zambelloni R, Connolly JPR, Uribe AH, Burgess K, Marquez R, Roe AJ. Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition. Mol Microbiol. 2017;105:606–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Linington RG, Robertson M, Gauthier A, Finlay BB, van Soest R, Andersen RJ. Caminoside A, an antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia. Org Lett. 2002;4:4089–92.

    CAS  PubMed  Google Scholar 

  137. Iwatsuki M, Uchida R, Yoshijima H, Ui H, Shiomi K, Kim YP, et al. Guadinomines, type III secretion system inhibitors, produced by Streptomyces sp. K01-0509. II: physico-chemical properties and structure elucidation. J Antibiot. 2008;61:230–6.

    CAS  Google Scholar 

  138. Schwiesow L, Lam H, Dersch P, Auerbuch V. Yersinia type III secretion system master regulator LcrF. J Bacteriol. 2016;198:604–14.

    CAS  PubMed Central  Google Scholar 

  139. Marsden AE, King JM, Spies MA, Kim OK, Yahr TL. Inhibition of Pseudomonas aeruginosa ExsA DNA-binding activity by N-hydroxybenzimidazoles. Antimicrob Agents Chemother. 2016;60:766–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Wang C, Liu X, Wang J, Zhou J, Cui Z, Zhang LH. Design and characterization of a polyamine derivative inhibiting the expression of type III secretion system in Pseudomonas aeruginosa. Sci Rep. 2016;6:30949. https://doi.org/10.1038/srep30949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Berube BJ, Murphy KR, Torhan MC, Bowlin NO, Williams JD, Bowlin TL, et al. Impact of type III secretion effectors and of phenoxyacetamide inhibitors of type III secretion on abscess formation in a mouse model of Pseudomonas aeruginosa infection. Antimicrob Agents Chemother. 2017;61:e01202–17. pii

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Guo Z, Li X, Li J, Yang X, Zhou Y, Lu C, Shen Y. Licoflavonol is an inhibitor of the type three secretion system of Salmonella enterica serovar Typhimurium. Biochem Biophys Res Commun. 2016;477:998–1004.

    CAS  PubMed  Google Scholar 

  143. Zetterstrom CE, Hasselgren J, Salin O, Davis RA, Quinn RJ, Sundin C, Elofsson M. The resveratrol tetramer (-)-hopeaphenol inhibits type III secretion in the gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa. PLoS One. 2013;8:e81969.

    PubMed  PubMed Central  Google Scholar 

  144. Zhang Y, Liu Y, Qiu J, Luo ZQ, Deng X. The herbal compound thymol protects mice from lethal infection by Salmonella Typhimurium. Front Microbiol. 2018;9:1022. https://doi.org/10.3389/fmicb.2018.01022

    Article  PubMed  PubMed Central  Google Scholar 

  145. Kimura K, Iwatsuki M, Nagai T, Matsumoto A, Takahashi Y, Shiomi K, Omura S, Abe A. A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium. J Antibiot. 2011;64:197–203.

    CAS  Google Scholar 

  146. McHugh RE, O’Boyle N, Connolly JPR, Hoskisson PA, Roe AJ. Characterization of the mode of action of aurodox, a type III secretion system inhibitor from Streptomyces goldiniensis. Infect Immun. 2019;87:e00595–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Dey S, Anbanandam A, Mumford BE, De Guzman RN. Characterization of small-molecule scaffolds that bind to the Shigella type III secretion system rotein IpaD. ChemMedChem. 2017;12:1534–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Tanaka T. Antraformin, a new inhibitor of Bacillus subtilis transformation. J Antibiot. 1975;28:567–72.

    CAS  Google Scholar 

  149. Lorenz MG, Wackernagel W. Bacterial gene transfer by natural genetic transformation in the environment. Microbiol Rev. 1994;58:563–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Blokesch M. Natural competence for transformation. Curr Biol. 2016;26:R1126–R1130.

    CAS  PubMed  Google Scholar 

  151. Fontaine L, Wahl A, Flechard M, Mignolet J, Hols P. Regulation of competence for natural transformation in streptococci. Infect Genet Evol. 2015;33:343–60.

    PubMed  Google Scholar 

  152. Saeki EK, Kobayashi RKT, Nakazato G. Quorum sensing system: target to control the spread of bacterial infections. Microb Pathog. 2020;142:104068.

    CAS  PubMed  Google Scholar 

  153. Abisado RG, Benomar S, Klaus JR, Dandekar AA, Chandler JR. Bacterial quorum sensing and microbial community interactions. mBio. 2018;9:e02331–17. https://doi.org/10.1128/mBio.02331-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. LaSarre B, Federle MJ. Exploiting quorum sensing to confuse bacterial pathogens. Microbiol Mol Biol Rev. 2013;77:73–111.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Kim CS, Gatsios A, Cuesta S, Lam YC, Wei Z, Chen H, et al. Characterization of autoinducer-3 structure and biosynthesis in E. coli. ACS Cent Sci. 2020;6:197–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Cugini C, Calfee MW, Farrow JM 3rd, Morales DK, Pesci EC, Hogan DA. Farnesol, a common sesquiterpene, inhibits PQS production in Pseudomonas aeruginosa. Mol Microbiol. 2007;65:896–906.

    CAS  PubMed  Google Scholar 

  157. Christensen QH, Grove TL, Booker SJ, Greenberg EP. A high-throughput screen for quorum-sensing inhibitors that target acyl-homoserine lactone synthases. Proc Natl Acad Sci USA. 2013;110:13815–20.

    CAS  PubMed  Google Scholar 

  158. Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev. 2010;34:426–44.

    CAS  PubMed  Google Scholar 

  159. Gutierrez JA, Crowder T, Rinaldo-Matthis A, Ho MC, Almo SC, Schramm VL. Transition state analogs of 5’-methylthioadenosine nucleosidase disrupt quorum sensing. Nat Chem Biol. 2009;5:251–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Shen G, Rajan R, Zhu J, Bell CE, Pei D. Design and synthesis of substrate and intermediate analogue inhibitors of S-ribosylhomocysteinase. J Med Chem. 2006;49:3003–11.

    CAS  PubMed  Google Scholar 

  161. Fetzner S. Quorum quenching enzymes. J Biotechnol. 2015;201:2–14.

    CAS  PubMed  Google Scholar 

  162. Murugayah SA, Gerth ML. Engineering quorum quenching enzymes: progress and perspectives. Biochem Soc Trans. 2019;47:793–800.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. de Nys R, Wright AD, Konig GM, Sticher O. New halogenated furanones from the marine alga Delisea pulchra (cf. fimbriata). Tetrahedron. 1993;49:11213–20.

    Google Scholar 

  164. Proctor CR, McCarron PA, Ternan NG. Furanone quorum-sensing inhibitors with potential as novel therapeutics against Pseudomonas aeruginosa. J Med Microbiol. 2020;69:195–206.

    CAS  PubMed  Google Scholar 

  165. Jakobsen TH, van Gennip M, Phipps RK, Shanmugham MS, Christensen LD, Alhede M, et al. Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing. Antimicrob Agents Chemother. 2012;56:2314–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Jakobsen TH, Warming AN, Vejborg RM, Moscoso JA, Stegger M, Lorenzen F, et al. A broad range quorum sensing inhibitor working through sRNA inhibition. Sci Rep. 2017;7:9857. https://doi.org/10.1038/s41598-017-09886-8

    Article  PubMed  PubMed Central  Google Scholar 

  167. Rasmussen TB, Skindersoe ME, Bjarnsholt T, Phipps RK, Christensen KB, Jensen PO, et al. Identity and effects of quorum-sensing inhibitors produced by Penicillium species. Microbiology. 2005;151:1325–40.

    CAS  PubMed  Google Scholar 

  168. Girennavar B, Cepeda ML, Soni KA, Vikram A, Jesudhasan P, Jayaprakasha GK, et al. Grapefruit juice and its furocoumarins inhibits autoinducer signaling and biofilm formation in bacteria. Int J Food Microbiol. 2008;125:204–8.

    CAS  PubMed  Google Scholar 

  169. Paczkowski JE, Mukherjee S, McCready AR, Cong JP, Aquino CJ, Kim H, et al. Flavonoids suppress Pseudomonas aeruginosa virulence through allosteric inhibition of quorum-sensing receptors. J Biol Chem. 2017;292:4064–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Vandeputte OM, Kiendrebeogo M, Rasamiravaka T, Stevigny C, Duez P, Rajaonson S, et al. The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa PAO1. Microbiology. 2011;157:2120–32.

    CAS  PubMed  Google Scholar 

  171. Vikram A, Jesudhasan PR, Jayaprakasha GK, Pillai SD, Patil BS. Citrus limonoids interfere with Vibrio harveyi cell-cell signalling and biofilm formation by modulating the response regulator LuxO. Microbiology. 2011;157:99–110.

    CAS  PubMed  Google Scholar 

  172. Kumar A, Sperandio V. Indole signaling at the host-microbiota-pathogen interface. mBio. 2019;10:e01031–19. https://doi.org/10.1128/mBio.01031-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kim J, Park W. Indole inhibits bacterial quorum sensing signal transmission by interfering with quorum sensing regulator folding. Microbiology. 2013;159:2616–25.

    CAS  PubMed  Google Scholar 

  174. Yang Q, Pande GSJ, Wang Z, Lin B, Rubin RA, Vora GJ, Defoirdt T. Indole signalling and (micro)algal auxins decrease the virulence of Vibrio campbellii, a major pathogen of aquatic organisms. Environ Microbiol. 2017;19:1987–2004.

    CAS  PubMed  Google Scholar 

  175. Tan SY, Chua SL, Chen Y, Rice SA, Kjelleberg S, Nielsen TE, et al. Identification of five structurally unrelated quorum-sensing inhibitors of Pseudomonas aeruginosa from a natural-derivative database. Antimicrob Agents Chemother. 2013;57:5629–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Starkey M, Lepine F, Maura D, Bandyopadhaya A, Lesic B, He J, et al. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity. PLoS Pathog. 2014;10:e1004321. https://doi.org/10.1371/journal.ppat.1004321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Choi H, Mascuch SJ, Villa FA, Byrum T, Teasdale ME, Smith JE, et al. Honaucins A-C, potent inhibitors of inflammation and bacterial quorum sensing: synthetic derivatives and structure-activity relationships. Chem Biol. 2012;19:589–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Mansson M, Nielsen A, Kjærulff L, Gotfredsen CH, Wietz M, Ingmer H, et al. Inhibition of virulence gene expression in Staphylococcus aureus by novel depsipeptides from a marine Photobacterium. Mar Drugs. 2011;9:2537–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Kjaerulff L, Nielsen A, Mansson M, Gram L, Larsen TO, Ingmer H, Gotfredsen CH. Identification of four new agr quorum sensing-interfering cyclodepsipeptides from a marine Photobacterium. Mar Drugs. 2013;11:5051–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Sully EK, Malachowa N, Elmore BO, Alexander SM, Femling JK, Gray BM, et al. Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathog. 2014;10:e1004174. https://doi.org/10.1371/journal.ppat.1004174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Salam AM, Quave CL. Targeting virulence in Staphylococcus aureus by chemical inhibition of the accessory gene regulator system in vivo. mSphere. 2018;3:e00500–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. D’Angelo F, Baldelli V, Halliday N, Pantalone P, Polticelli F, Fiscarelli E, et al. Identification of FDA-Approved drugs as antivirulence agents targeting the pqs quorum-sensing system of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018;62:e01296–18. https://doi.org/10.1128/AAC.01296-18

    Article  PubMed  PubMed Central  Google Scholar 

  183. Hornef M. Pathogens, commensal symbionts, and pathobionts: discovery and functional effects on the host. ILAR J. 2015;56:159–62.

    CAS  PubMed  Google Scholar 

  184. Cerf-Bensussan N, Gaboriau-Routhiau V. The immune system and the gut microbiota: friends or foes? Nat Rev Immunol. 2010;10:735–44.

    CAS  PubMed  Google Scholar 

  185. Hotinger JA, May AE. Animal models of Type III secretion system-mediated pathogenesis. Pathogens. 2019;8:257. https://doi.org/10.3390/pathogens8040257

    Article  CAS  PubMed Central  Google Scholar 

  186. Kiga K, Tan XE, Ibarra-Chavez R, Watanabe S, Aiba Y, Satoʼo Y, et al. Development of CRISPR-Cas13a-based antimicrobials capable of sequence-specific killing of target bacteria. Nat Commun. 2020;11:2934. https://doi.org/10.1038/s41467-020-16731-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. HO Bio Institute, Tokyo, Japan

    Hiroshi Ogawara

  2. Department of Biochemistry, Meiji Pharmaceutical University, Tokyo, Japan

    Hiroshi Ogawara

Authors
  1. Hiroshi Ogawara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroshi Ogawara.

Ethics declarations

Conflict of interest

The author declares that he has no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ogawara, H. Possible drugs for the treatment of bacterial infections in the future: anti-virulence drugs. J Antibiot 74, 24–41 (2021). https://doi.org/10.1038/s41429-020-0344-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-020-0344-z

This article is cited by

Search

Advanced search

Quick links