1887

Abstract

A bromotyrosine alkaloid family of antimicrobial agents was synthesized using the known structure of a natural inhibitor of the mycobacterial mycothiol -conjugate amidase (MCA) as a template. This series of compounds represents a novel class of anti-infective agents against Gram-positive pathogens, including mycobacteria and meticillin- and vancomycin-resistant . The fact that these compounds are active against mycobacterial strains in which the MCA gene is deleted and against Gram-positive bacteria lacking mycothiol suggests the existence of an alternative target for these compounds. One member of this family, EXEG1706, was identified as the lead compound possessing low MICs (2·5–25 μg ml) for several clinical isolates, whilst having low toxicity for THP-1 monocytes and macrophages.

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2006-04-01
2024-03-29
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References

  1. Arad D., Av-Gay Y. 2003; Antimicrobial compounds against Staphylococci, Mycobacteria and other infectious agents. US patent application WO 2004012506 and WO 2003087127
  2. Bartley J. 2002; First case of VRSA identified in Michigan. Infect Control Hosp Epidemiol 23:480
    [Google Scholar]
  3. Basta S., Knoetig S. M., Spagnuolo-Weaver M., Allan G., McCullough K. C. 1999; Modulation of monocytic cell activity and virus susceptibility during differentiation into macrophages. J Immunol 162:3961–3969
    [Google Scholar]
  4. Casewell M. W., Hill R. L. 1986; The carrier state: methicillin-resistant Staphylococcus aureus . J Antimicrob Chemother 18 (Suppl. A):1–12 [CrossRef]
    [Google Scholar]
  5. Cassone M., Campanile F., Pantosti A., Venditti M., Stefani S. 2004; Identification of a variant “Rome clone” of methicillin-resistant Staphylococcus aureus with decreased susceptibility to vancomycin, responsible for an outbreak in an intensive care unit. Microb Drug Resist 10:43–49 [CrossRef]
    [Google Scholar]
  6. Coccia E. M., Del Russo N., Stellacci E., Testa U., Marziali G., Battistini A. 1999; STAT1 activation during monocyte to macrophage maturation: role of adhesion molecules. Int Immunol 11:1075–1083 [CrossRef]
    [Google Scholar]
  7. Dye C., Scheele S., Dolin P., Pathania V., Raviglione M. C. 1999; Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. . JAMA 282:677–686 [CrossRef]
    [Google Scholar]
  8. Gessani S., Testa U., Varano B. & 7 other authors; 1993; Enhanced production of LPS-induced cytokines during differentiation of human monocytes to macrophages. Role of LPS receptors. . J Immunol 151:3758–3766
    [Google Scholar]
  9. Kende A. S., Lan J., Fan J. 2004; Total synthesis of a dibromotyrosine alkaloid inhibitor of mycothiol S-conjugate amidase. Tetrahedron Lett 45:133–135 [CrossRef]
    [Google Scholar]
  10. Kluytmans J. A., Mouton J. W., Ijzerman E. P., Vandenbroucke-Grauls C. M., Maat A. W., Wagenvoort J. H., Verbrugh H. A. 1995; Nasal carriage of Staphylococcus aureus as a major risk factor for wound infections after cardiac surgery. J Infect Dis 171:216–219 [CrossRef]
    [Google Scholar]
  11. Lowy F. D. 1998; Staphylococcus aureus infections. N Engl J Med 339:520–532 [CrossRef]
    [Google Scholar]
  12. Mallaval F. O., Carricajo A., Delavenna F. & 7 other authors; 2004; Detection of an outbreak of methicillin-resistant Staphylococcus aureus with reduced susceptibility to glycopeptides in a French hospital. Clin Microbiol Infect 10:459–461 [CrossRef]
    [Google Scholar]
  13. Maynes J. T., Garen C., Cherney M. M., Newton G., Arad D., Av-Gay Y., Fahey R. C., James M. N. 2003; The crystal structure of 1-d- myo -inosityl 2-acetamido-2-deoxy- α -d-glucopyranoside deacetylase (MshB) from Mycobacterium tuberculosis reveals a zinc hydrolase with a lactate dehydrogenase fold. J Biol Chem 278:47166–47170 [CrossRef]
    [Google Scholar]
  14. McCarthy A. A., Knijff R., Peterson N. A., Baker E. N. 2003; Crystallization and preliminary X-ray analysis of N -acetyl-1-d- myo -inosityl-2-deoxy- α -d-glucopyranoside deacetylase (MshB) from Mycobacterium tuberculosis . Acta Crystallogr D Biol Crystallogr 59:2316–2318 [CrossRef]
    [Google Scholar]
  15. National Committee for Clinical Laboratory Standards 1993 Performance standards for antimicrobial susceptibility tests for bacteria that grow aerobically , approved standard M7-T2, 2nd edn. Villanova, PA: National Committee for Clinical Laboratory Standards;
    [Google Scholar]
  16. Negi S. S., Gupta S., Lal S. 2003; Drug resistance in tuberculosis in Delhi: a 2 year profile (2001–2002). J Commun Dis 35:74–81
    [Google Scholar]
  17. Newton G. L., Arnold K., Price M. S. & 7 other authors; 1996; Distribution of thiols in microorganisms: mycothiol is a major thiol in most actinomycetes. J Bacteriol 178:1990–1995
    [Google Scholar]
  18. Newton G. L., Av-Gay Y., Fahey R. C. 2000; A novel mycothiol-dependent detoxification pathway in mycobacteria involving mycothiol S -conjugate amidase. Biochemistry 39:10739–10746 [CrossRef]
    [Google Scholar]
  19. Nicholas G. M., Newton G. L., Fahey R. C., Bewley C. A. 2001; Novel bromotyrosine alkaloids: inhibitors of mycothiol S -conjugate amidase. Org Lett 3:1543–1545 [CrossRef]
    [Google Scholar]
  20. Nicholas G. M., Eckman L. L., Ray S., Hughes R. O., Pfefferkorn J. A., Barluenga S., Nicolaou K. C., Bewley C. A. 2002; Bromotyrosine-derived natural and synthetic products as inhibitors of mycothiol- S -conjugate amidase. Bioorg Med Chem Lett 12:2487–2490 [CrossRef]
    [Google Scholar]
  21. Pick N., Cameron S., Arad D., Av-Gay Y. 2004; Screening of compounds toxicity against human monocytic cell line-THP-1 by flow cytometry. Biol Proced Online 6:220–225 [CrossRef]
    [Google Scholar]
  22. Rawat M., Newton G., Ko M., Martinez G., Fahey R. C., Av-Gay Y. 2002; Mycothiol-deficient Mycobacterium smegmatis mutants are hypersensitive to alkylating agents, free radicals, and antibiotics. Antimicrob Agents Chemother 46:3348–3355 [CrossRef]
    [Google Scholar]
  23. Rawat M., Kovacevic S., Billman-Jacobe H., Av-Gay Y. 2003; Inactivation of mshB , a key gene in the mycothiol biosynthesis pathway in Mycobacterium smegmatis . Microbiology 149:1341–1349 [CrossRef]
    [Google Scholar]
  24. Rawat M., Uppal M., Newton G., Steffek M., Fahey R. C., Av-Gay Y. 2004; Targeted mutagenesis of the Mycobacterium smegmatis mca gene, encoding a mycothiol-dependent detoxification protein. J Bacteriol 186:6050–6058 [CrossRef]
    [Google Scholar]
  25. Sanford M. D., Widmer A. F., Bale M. J., Jones R. N., Wenzel R. P. 1994; Efficient detection and long-term persistence of the carriage of methicillin-resistant Staphylococcus aureus . Clin Infect Dis 19:1123–1128 [CrossRef]
    [Google Scholar]
  26. Schwalbe R. S., Stapleton J. T., Gilligan P. H. 1987; Emergence of vancomycin resistance in coagulase-negative staphylococci. N Engl J Med 316:927–931 [CrossRef]
    [Google Scholar]
  27. Tuazon C. U., Sheagren J. N. 1974; Increased rate of carriage of Staphylococcus aureus among narcotic addicts. J Infect Dis 129:725–727 [CrossRef]
    [Google Scholar]
  28. Tuazon C. U., Perez A., Kishaba T., Sheagren J. N. 1975; Staphylococcus aureus among insulin-injecting diabetic patients. An increased carrier rate. JAMA 231:1272 [CrossRef]
    [Google Scholar]
  29. Wagner J., Kallen J., Ehrhardt C., Evenou J. P., Wagner D. 1998; Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors. J Med Chem 41:3664–3674 [CrossRef]
    [Google Scholar]
  30. Weinke T., Schiller R., Fehrenbach F. J., Pohle H. D. 1992; Association between Staphylococcus aureus nasopharyngeal colonization and septicemia in patients infected with the human immunodeficiency virus. Eur J Clin Microbiol Infect Dis 11:985–989 [CrossRef]
    [Google Scholar]
  31. Wenzel R. P., Perl T. M. 1995; The significance of nasal carriage of Staphylococcus aureus and the incidence of postoperative wound infection. J Hosp Infect 31:13–24 [CrossRef]
    [Google Scholar]
  32. World Health Organization 2002 Tuberculosis , WHO fact sheet no 104 Geneva: World Health Organization;
    [Google Scholar]
  33. Yanisch-Perron C., Vieira J., Messing J. 1985; Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mp18 and pUC19 vectors. Gene 33:103–119 [CrossRef]
    [Google Scholar]
  34. Yu V. L., Goetz A., Wagener M., Smith P. B., Rihs J. D., Hanchett J., Zuravleff J. J. 1986; Staphylococcus aureus nasal carriage and infection in patients on hemodialysis. Efficacy of antibiotic prophylaxis. . N Engl J Med 315:91–96 [CrossRef]
    [Google Scholar]
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