Antibacterial agents reducing the risk of resistance development | CMAC

Antibacterial agents reducing the risk of resistance development

Clinical Microbiology and Antimicrobial Chemotherapy. 2021; 23(2):184-194

​ Zigangirova N.A., Lubeneс N.L., Zaitsev A.V., Pushkar D.Yu.
10.36488/cmac.2021.2.184-194
virulence factors chronic infections therapy prevention antivirulence drug
Section
Antimicrobials
Type
Review
Publication
Clinical Microbiology and Antimicrobial Chemotherapy. 2021; 23(2):184-194

Abstract

The most important goal of medical microbiology in terms of treating infectious diseases nowadays and in the coming decades will be the development of antibacterial agents that are effective against resistant pathogens and reduce the selection of antimicrobial resistance. In this regard, along with the search for new classic antibiotics, it is necessary to develop alternative strategies. Virulence factors that determine the key stages of the infection process, both acute and chronic, including adhesins, toxins, bacterial quorum sensing, secretory systems, could be potential targets. The strategy for the development of antivirulence drugs is already showing its potential in the treatment of nosocomial, complicated and chronic infections as part of complex therapy and for prevention. The review presents the results of studies of drugs that have already shown efficacy in model infections in animals or have either passed to the stage of clinical trials or have already been registered. The development of effective combination therapy regimens will minimize the risks of acquiring resistance.

Nailya А. Zigangirova

N.F. Gamaleya National Research Center of Epidemiology and Microbiology, Moscow, Russia

Lubeneс N.L.

N.F. Gamaleya National Research Center of Epidemiology and Microbiology, Moscow, Russia

Zaitsev A.V.

A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia

Pushkar D.Yu.

A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia

  • 1. Clatworthy A.E., Pierson E., Hung D.T. Targeting virulence: a new paradigm for antimicrobial therapy. Nat Chem Biol. 2007;3:541-548. DOI: 10.1038/nchembio.2007.24
  • 2. Czaplewski L., Bax R., Clokie M., Dawson M., Fairhead H., Fischetti V. A.Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect Dis. 2016;16(2):239-251. DOI: 10.1016/S1473-3099(15)00466-1
  • 3. Munguia J., Nizet V. Pharmacological targeting of the hostpathogen interaction: alternatives to classical antibiotics to combat drug-resistant superbugs. Trends Pharmacol Sci. 2017;38:473-488. DOI: 10.1016/j.tips.2017.02.003
  • 4. Allen R.C., Popat R., Diggle S.P., Brown S.P. Targeting virulence: can we make evolution-proof drugs? Nat Rev Microbiol. 2014;12:300-308. DOI: 10.1038/nrmicro3232
  • 5. Payne D.J., Gwynn M. N., Holmes D.J., Pompliano D.L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6:2940. DOI: 10.1038/nrd2201
  • 6. Theuretzbacher U., Piddock L.J.V. Non-traditional antibacterial therapeutic options and challenges. Cell Host Microbe. 2019;26:61-72. DOI: 10.1016/j.chom.2019.06.004
  • 7. Totsika M. Benefits and challenges of antivirulence antimicrobials at the dawn of the post-antibiotic era. Curr Medicin Chem. 2016;6:30-37. DOI: 10.2174/2210303106666160506120057
  • 8. Dickey S.W., Cheung G.Y.C., Otto M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov. 2017;16(7):457-471. DOI: 10.1038/nrd.2017.23, 457
  • 9. Rasko D.A., Sperandio V. Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov. 2010;9(2):117-128. DOI: 10.1038/nrd3013
  • 10. Korneev I.A., Alekseeva T.A., Kogan M.I., Pushkar' D.Y. Epidemiology of urinary disorders in men in the Russian Federation. Urologiia. 2016;(2 Suppl 2):70-75. Russian.
  • 11. Flores-Mireles A.L., Walker J. N., Caparon M., Hultgren S.J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015;13(5):269-284. DOI: 10.1038/nrmicro3432
  • 12. Spaulding C.N., Hultgren S.J. Adhesive pili in UTI pathogenesis and drug development. Pathogens. 2016;5(1):30. DOI: 10.3390/pathogens5010030
  • 13. Han Z., Pinkner J.S., Ford B., Obermann R., Nolan W., Wildman S.A., et al. Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J Med Chem. 2010;53(12):4779-4792. DOI: 10.1021/jm100438s
  • 14. Totsika M., Kostakioti M., Hannan T.J., Upton M., Beatson S.A., Janetka J.W., et al. A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. J Infect Dis. 2013;208(6):921-928. DOI: 10.1093/infdis/jit245
  • 15. Maddirala A.R., Klein R., Pinkner J.S., Kalas V., Hultgren S.J., Janetka J.W. Biphenyl Gal and GalNAc FmlH lectin antagonists of uropathogenic E. coli (UPEC): optimization through iterative rational drug design. J Med Chem. 2019;62:467-479. DOI: 10.1021/acs.jmedchem.8b01561
  • 16. Kalas V., Hibbing M.E., Maddirala A.R., Chugani R., Pinkner J.S., Mydock-McGrane L.K., et al. Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection. Proc Natl Acad Sci USA. 2018;115(12):E2819-E2828. DOI: 10.1073/pnas.1720140115
  • 17. Cascioferro S., Totsika M., Schillaci D. Sortase A. An ideal target for anti-virulence drug development. Microb Pathog. 2014;77:105-112. DOI: 10.1016/j.micpath.2014.10.007
  • 18. Zhang J., Liu H., Zhu K., Gong S., Dramsi S., Wang Y.T., et al. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase. Proc Natl Acad Sci USA. 2014;111(37):13517-13522. DOI: 10.1073/pnas.1408601111
  • 19. Bi C., Dong X., Zhong X., Cai H., Wang D., Wang L. Acacetin protects mice from Staphylococcus aureus bloodstream infection by inhibiting the activity of sortase A. Molecules. 2016;21:1285-1296. DOI: 10.3390/molecules21101285
  • 20. Kong C., Neoh H.M., Nathan S. Targeting Staphylococcus aureus toxins: a potential form of anti-virulence therapy. Toxins. 2016;8:72. DOI: 10.3390/toxins8030072
  • 21. Sharma-Kuinkel B.K., Wu Y., Tabor D.E., Mok H., Sellman B.R., Jenkins A., et al. Characterization of alphatoxin hla gene variants, alpha-toxin expression levels, and levels of antibody to alpha-toxin in hemodialysis and postsurgical patients with Staphylococcus aureus bacteremia. J Clin Microbiol. 2015;53(1):227-236. DOI: 10.1128/JCM.02023-14
  • 22. Yu X.Q., Robbie G.J., Wu Y., Esser M.T., Jensen K., Schwartz H.I., et al. Safety, tolerability, and pharmacokinetics of MEDI4893, an investigational, extended-half-life, antiStaphylococcus aureus alpha-toxin human monoclonal antibody, in healthy adults. Antimicrob Agents Chemother. 2017;61(1):e01020-16. DOI: 10.1128/AAC.01020-16
  • 23. Ruzin A., Wu Y., Yu L., Yu X-Q., Tabor D.E., Mok H., et al. Characterisation of anti-alpha toxin antibody levels and colonisation status after administration of an investigational human monoclonal antibody, MEDI4893, against Staphylococcus aureus alpha toxin. Clin Transl Immunology. 2018;e1009. DOI: 10.1002/cti2.1009
  • 24. Rouha H., Badarau A., Visram Z.C., Battles M.B., Prinz B., Magyarics Z., et al. Five birds, one stone: neutralization of alpha-hemolysin and 4 bi­component leukocidins of Staphylococcus aureus with a single human monoclonal antibody. MAbs. 2015;7(1):243-254. DOI: 10.4161/19420862.2014.985132
  • 25. Smith R.S., Iglewski B.H. P. aeruginosa quorum-sensing systems and virulence. Curr Opin Microbiol. 2003;6(1):5660. DOI: 10.1016/s1369-5274(03)00008-0
  • 26. Martínez O.F., Cardoso M.H., Ribeiro S.M., Franco O.L. Recent advances in anti-virulence therapeutic strategies with a focus on dismantling bacterial membrane microdomains, toxin neutralization, quorum-sensing interference and biofilm inhibition. Front Cell Infect Microbiol. 2019;9:74. DOI: 10.3389/fcimb.2019.00074
  • 27. Jiang Q., Chen J., Yang C., Yin Y., Yao K. Quorum sensing: a prospective therapeutic target for bacterial diseases. Biomed Res Int. 2019;2019:2015978. DOI: 10.1155/2019/2015978
  • 28. Amara N., Gregor R., Rayo J., Dandela R., Daniel E., Liubin N., et al. Fine-tuning covalent inhibition of bacterial quorum sensing. Chembiochem. 2016;17:825-835. DOI: 10.1002/cbic.201500676
  • 29. Defoirdt T. Quorum-sensing systems as targets for antivirulence therapy. Trends Microbiol. 2017;26:313328. DOI: 10.1016/j.tim.2017.10.005
  • 30. Eickhoff M.J., Bassler B.L. SnapShot: bacterial quorum sensing. Cell. 2018;174(5):1328-1328.e1. DOI: 10.1016/j.cell.2018.08.003
  • 31. Bjarnsholt T., Jensen P.Ø., Rasmussen T. B., Christophersen L., Calum H., Hentzer M., et al. Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections. Microbiology. 2005;151:38733880. DOI: 10.1099/mic.0.27955-0
  • 32. Kalia V.C. Quorum sensing inhibitors: an overview. Biotechnol Adv. 201;31:224-245. DOI: 10.1016/j.biotechadv.2012.10.004
  • 33. Hraiech S., Hiblot J., Lafleur J., Lepidi H., Papazian L., Rolain J.-M., et al. Inhaled lactonase reduces Pseudomonas aeruginosa quorum sensing and mortality in rat pneumonia. PLoS One. 2014;9:e107125. DOI: 10.1371/journal.pone.0107125
  • 34. Praneenararat T., Palmer A.G., Blackwell H.E. Chemical methods to interrogate bacterial quorum sensing pathways. Org Biomol Chem. 2012;10(41):8189-8199. DOI: 10.1039/c2ob26353j
  • 35. Furiga A., Lajoie B., Hage S.El, Baziard G., Roques C. Impairment of Pseudomonas aeruginosa biofilm resistance to antibiotics by combining the drugs with a new quorum-sensing inhibitor. Antimicrob Agents Chemother. 2015;60(3):1676-86. DOI: 10.1128/AAC.02533-15
  • 36. Soheili V., Tajani A.S., Ghodsi R., Bazzaz B.S.F. Anti-PqsR compounds as next-generation antibacterial agents against Pseudomonas aeruginosa: a review. Eur J Med Chem. 2019;172:26-35. DOI: 10.1016/j.ejmech.2019.03.049
  • 37. Paczkowski E., Mukherjee S., McCready A.R., Cong J.P., Aquino C.J., Kim H., et al. Flavonoids suppress Pseudomonas aeruginosa virulence through allosteric inhibition of quorumsensing receptors. J Biol Chem. 2017;292(10):40644076. DOI: 10.1074/jbc.M116.770552
  • 38. Geske G.D., O’Neill J.C., Miller D.M., Mattmann M.E., Blackwell H.E. Modulation of bacterial quorum sensing with synthetic ligands: systematic evaluation of N-acylated homoserine lactones in multiple species and new insights into their mechanisms of action. J Am Chem Soc. 2007;129(44):13613-13625. DOI: 10.1021/ja074135h
  • 39. Kai T., Tateda K., Kimura S., Ishii Y., Ito H., Yoshida H., et al. A low concentration of azithromycin inhibits the mRNA expression of N­acyl homoserine lactone synthesis enzymes, upstream of lasI or rhlI, in Pseudomonas aeruginosa. Pulm Pharmacol. 2009;22(6):483-486. DOI: 10.1016/j.pupt.2009.04.004
  • 40. D’Angelo F., Baldelli V., Halliday N., Pantalone P., Polticelli F., Fiscarelli E., et al. Identification of FDAapproved drugs as antivirulence agents targeting the pqs quorum-sensing system of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018;62(11). pii: e0129618. DOI: 10.1128/AAC.01296-18
  • 41. 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(8):e1004321. DOI: 10.1371/journal.ppat.1004321
  • 42. Sully E.K., Malachowa N., Elmore B.O., Alexander S.M., Femling J.K., Gray B.M., et al. Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathog. 2014;10(6):e1004174. DOI: 10.1371/journal.ppat.1004174
  • 43. Luo J., Dong B., Wang K., Cai S., Liu T., Cheng X., et al. Baicalin inhibits biofilm formation, attenuates the quorum sensing-controlled virulence and enhances Pseudomonas aeruginosa clearance in a mouse peritoneal implant infection model. PLoS One. 2017;12(4):e0176883. DOI: 10.1371/journal.pone.0176883
  • 44. Qvortrup K., Hultqvist L.D., Nilsson M., Jakobsen T.H., Jansen C.U., Uhd J., et al. Small molecule anti-biofilm agents developed on the basis of mechanistic understanding of biofilm formation. Front Chem. 2019;7:742. DOI: 10.3389/fchem.2019.00742
  • 45. Skariyachan S., Sridhar V.S., Packirisamy S., Kumargowda S.T., Challapilli S.B. Recent perspectives on the molecular basis of biofilm formation by Pseudomonas aeruginosa and approaches for treatment and biofilm dispersal. Folia Microbiol (Praha). 2018;63(4):413-432. DOI: 10.1007/s12223-018-0585
  • 46. Maunders E., Welch M. Matrix exopolysaccharides; the sticky side of biofilm formation. FEMS Microbiol Lett. 2017;364(13):fnx120. DOI: 10.1093/femsle/fnx120
  • 47. Deng W., Marshall N.C., Rowland J.L., McCoy J.M., Worrall L.J., Santos A.S., et al. Assembly, structure, function and regulation of type III secretion systems. Nat Rev Microbiol. 2017;15(6):323-337. DOI: 10.1038/nrmicro.2017.20
  • 48. Galan J.E., Lara-Tejero M., Marlovits T.C., Wagner S. Bacterial type III secretion systems: specialized nanomachines for protein delivery into target cells. Annu Rev Microbiol. 2014;68:415-438. DOI: 10.1146/annurev-micro-092412-155725
  • 49. Fasciano A.C., Shaban L., Mecsas J. Promises and challenges of the type three secretion system injectisome as an antivirulence target. EcoSal Plus. 2019;8(2). DOI: 10.1128/ecosalplus.ESP-0032-2018
  • 50. Charro N., Mota L.J. Approaches targeting the type III secretion system to treat or prevent bacterial infections. Expert Opin Drug Discov. 2015;10(4):373-387. DOI: 10.1517/17460441.2015.1019860
  • 51. Duncan M.C., Linington R.G., Auerbuch V. Chemical inhibitors of the type three secretion system: disarming bacterial pathogens. Antimicrob Agents Chemother. 2012;56(11):5433-5441. DOI: 10.1128/AAC.00975-12
  • 52. Kauppi A.M., Nordfelth R., Uvell H., Wolf-Watz H., Elofsson M. Targeting bacterial virulence: inhibitors of type III secretion in Yersinia. Chem Biol. 2003;10(3):241-249. DOI: 10.1016/s1074-5521(03)00046-2
  • 53. Anantharajah A., Buyck J.M., Sundin C., Tulkens P.M., Mingeot-Leclercq M.P., Van Bambeke F. Salicylidene acylhydrazides and hydroxyquinolines act as inhibitors of type three secretion systems in Pseudomonas aeruginosa by distinct mechanisms. Antimicrob Agents Chemother. 2017;61(6). pii: e02566-16. DOI: 10.1128/AAC.02566-16
  • 54. Uusitalo P., Hägglund U., Rhöös E., Scherman Norberg H., Elofsson M., Sundin C. The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo. J Antibiot (Tokyo). 2017;70(9):937-943. DOI: 10.1038/ja.2017.64
  • 55. Anantharajah A., Faure E., Buyck J.M., Sundin C., Lindmark T., Mecsas J., et al. Inhibition of the injectisome and flagellar type iii secretion systems by INP1855 impairs Pseudomonas aeruginosa pathogenicity and inflammasome activation. J Infect Dis. 2016;214(7):1105-1116. DOI: 10.1093/infdis/jiw295
  • 56. DiGiandomenico A., Keller A.K., Gao C., Rainey G.J., Warrener P., Camara M.M., et al. A multifunctional bispecific antibody protects against Pseudomonas aeruginosa. Sci Transl Med. 2014;6(262):262ra155. DOI: 10.1126/scitranslmed.3009655
  • 57. Le H.N., Tran V.G., Vu T.T., Gras E., Le V.T.M., Pinheiro M.G., et al. Treatment efficacy of MEDI3902 in Pseudomonas aeruginosa bloodstream infection and acute pneumonia rabbit models. Antimicrob Agents Chemother. 2019;63(8). pii: e00710-19. DOI: 10.1128/AAC.00710-19
  • 58. Zigangirova N.A., Zayakin E.S., Kapotina L.N., Kost E.A., Didenko L.V., Davydova D.Y., et al. Development of chlamydial type III secretion system inhibitors for suppression of acute and chronic forms of chlamydial infection. Acta Naturae. 2012;4(2):87-97. PMID: 22880162
  • 59. Sheremet A.B., Zigangirova N.A., Zayakin E.S., Luyksaar S.I., Nesterenko L.N., Gintzburg A.L., et al. Small molecule inhibitor of type three secretion system belonging to a class 2, 4-disubstituted-4H-[1, 3, 4]-thiadiazine-5-ones improves survival and decreases bacterial loads in an airway Pseudomonas aeruginosa infection in mice. Biomed Res Int. 2018;2018:5810767. DOI: 10.1155/2018/5810767
  • 60. Koroleva E.A., Kobets N.V., Zayakin E.S., Luyksaar S.I., Zigangirova N.A. Small molecule inhibitor of type three secretion suppresses acute and chronic Chlamydia trachomatis infection in a novel urogenital chlamydia model. Biomed Res Int. 2015;484853. DOI: 10.1155/2015/484853
  • 61. Zigangirova N.A., Kost E.A., Didenko L.V., Kapotina L.N., Zayakin E.S., Luyksaar S.I., et al. A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis. J Med Microbiol. 2016;65(1):91-98. DOI: 10.1099/jmm.0.000189
  • 62. Nesterenko L.N., Zigangirova N.A., Zayakin E.S., Luyksaar S.I., Kobets N.V., Balunets D.V., et al. A smallmolecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones suppresses Salmonella infection in vivo. J Antibiot (Tokyo). 2016;69(6):422-427. DOI: 10.1038/ja.2015.131
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