Development of Antivirulence Compounds: A Biochemical Review
There is an urgent requirement for new anti‐infective compounds that can be used to prevent or treat bacterial pathogens. In particular, Gram‐negative pathogens, which are most commonly associated with hospital‐acquired infections, are of major concern. In this review, we cover recent developments i...
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| Published in | Chemical biology & drug design Vol. 85; no. 1; pp. 43 - 55 |
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| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Blackwell Publishing Ltd
01.01.2015
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| Subjects | |
| Online Access | Get full text |
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| Summary: | There is an urgent requirement for new anti‐infective compounds that can be used to prevent or treat bacterial pathogens. In particular, Gram‐negative pathogens, which are most commonly associated with hospital‐acquired infections, are of major concern. In this review, we cover recent developments in the screening and testing of new anti‐infective compounds that interfere with aspects of bacterial pathogenicity. This so‐called antivirulence approach is very different to traditional antibiotic development and testing. Moreover, antivirulence compounds vary considerably in their chemical structures, ranging from small compounds to large natural products. The challenge of understanding the precise mechanism of action of any such compound is also highlighted.
A wide range of anti‐infective compounds targeting virulence factor expression or function have been developed. The compounds range from small molecules to complex natural products: there is enormous diversity. The vast majority of these have resulted from high throughput screens and lack detailed mechanistic knowledge of their mode of action. |
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| Bibliography: | Figure S1. Cartoon showing basic features of the T3SS.Figure S2. Caminosides structures.Figure S3. Aurodox 5 and the guadinomines.Figure S4. Cytosporone B 18 and derivatives. (−)-hopeaphenol 20.Figure S5. Marine derivatives Piericidin A1 and Mer-A 2026B.Figure S6. Chemical structures (23-27).Figure S7. 2-Imino-5-arylidene thiazolidinone structure, SAR study, and %SipA secretion following treatment with 380 μm of drug.Figure S8. General synthetic route for 2-imino-5-arylidene thiazolidinone (R and R1 = Aryl or Alkyl).Figure S9. Chemical structures of the candidates identified by Kauppi et al. (24).Figure S10. SA compounds used by Hudson et al. (27), Negrea et al. (28), and Veenendaal et al. (29).Figure S11. Chemical structure of 52 and its Affi-Gel labeled derivative.Figure S12. QseC pathways.Figure S13. LED209 chemical structure.Figure S14. LED209 synthesis.Figure S15. ToxT homodimerization and mode of action of 1virstatin proposed by Mekalonos et al.Figure S16. Virstatin.Figure S17. Virstatin synthesis.Figure S18. Mode of action of the anthrax toxin.Figure S19. Lead optimization by Chapman et al.Figure S20. General synthetic route for hydroxamic acid 70.Figure S21. Chemical structure (75-79).Figure S22. Mechanism for the pilus formation.Figure S23. Chemical structures of tyrosine derivatives (80) and pyridinone derivatives (81).Figure S24. Synthetic route for tyrosine and pyridinone derivatives.Figure S25. Structure of C6 substitued pyridones.Figure S26. Microwave Mannich reaction.Figure S27. Scheme of the crystal structure of pyridones 90 bound to the chaperone-subunit complex.Figure S28. Synthesis of C2 substituted pyridones.Figure S29. Flattened C2 derivatives.Figure S30. Synthesis for other C2 substitued pyridones and carboxylic acid bioisostere. ArticleID:CBDD12430 ark:/67375/WNG-85W1JPZX-2 istex:86A2133A618F74734FBC01DC2D94836E07CC6CA6 University of Glasgow ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Review-1 |
| ISSN: | 1747-0277 1747-0285 |
| DOI: | 10.1111/cbdd.12430 |