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Chapter 40 : From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy

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From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, Page 1 of 2

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Abstract:

While the authors were exploring the general chemistry of the tetracyclines, semisynthetic reactions were applied to favorable antibacterial positions of the naphthacene ring, in particular the aromatic D-ring and the upper peripheral region spanning carbons C5 to C9. They felt that the tetracyclines had been neglected in the area of semisynthesis and were confident that even more potent tetracyclines could be synthesized, particularly against antibiotic-resistant bacteria. It was the application of more modern reactions to the tetracyclines from our medicinal chemistry laboratory and biology advances derived from the Stuart B. Levy laboratory and the study of the multiple antibiotic resistance (MAR) locus that led to the start of Paratek Pharmaceuticals in Boston, Mass., in the summer of 1996. Other reactions and novel tetracycline products soon followed C7 diazo tetracyclines reacted similarly, yielding C7 alkenyl derivatives, while substituting phenylboronic acids led to other novel classes of tetracyclines, the C7 and C9 phenyl tetracyclines. The impact of antibacterial resistance on our supply of antibiotics initiated the search for the mechanisms of antibiotic resistance, and advances in our understanding of these mechanisms have led to the development of more potent drugs across most, if not all, antibiotic families. The efforts of Levy and his colleagues have, over the years, made significant advances in the understanding of resistance and in the identification and characterization of efflux of antibiotics by resistant bacteria.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40

Key Concept Ranking

Antibacterial Agents
0.47474906
Tetracycline Antibiotics
0.46904248
Bacterial Proteins
0.4285875
Urinary Tract Infections
0.40852672
0.47474906
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Figures

Image of Figure 1.
Figure 1.

(back to front) Richard Petrucci, Laura McMurry and Stuart Levy in the laboratory performing the everted membrane vesicle assay sometime in the 1970s.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
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Image of Figure 2.
Figure 2.

The structural locants of the tetracycline naphthacene ring system and structural features needed for optimal efflux inhibition in vesicles and possessing Tet(B) proteins. Region outlined in solid lines indicates features needed for optimal efflux inhibition. Dashed line shows region that can be chemically modified for optimal efflux inhibition.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
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Image of Figure 3.
Figure 3.

13-Alkylthio derivatives of methacycline. A) 13-propylthio-5-OH tetracycline and B) 13-cyclopentylthio-5-OH tetracycline (13-CPTC).

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
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Image of Figure 4.
Figure 4.

Reversing H-Tc efflux in E. coli D1-209 cells possessing the Tet(B) protein pre-incubated with 13-CPTC (40 μM, ● ), or without 13-CPTC (○). A rapid increase of intracellular H-Tc occurs after addition of 13-CPTC (40 μM, ■) in glucose activated cells.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
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Image of Figure 5.
Figure 5.

Novel tetracyclines synthesized by transition metal catalyzed reactions producing C7 and C9 derivatives possessing structural diversity. Intermediate tetracyclines can form alkenes, alkynes, phenyl and heteroaromatic and carbonyl derivatives, among others.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
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Image of Figure 6.
Figure 6.

Synthesis pathway for the 9-aminomethyl minocyclines and the synthesis of derivatives, notably 7-dimethylamino-2,2-(dimethylpropyl)aminomethyl minocycline, designated PTK 0796.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
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References

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15. Endermann, R.,, C. H. Ladel,, H. Broetz-Oesterhelt,, and H. Labischinski. 2004. BAY 73-7388 is highly efficacious in animal models of intra-abdominal infections caused by a range of aerobic and anaerobic organisms, including VRE. 14th European Congress of Clinical Microbiology and Infectious Diseases. Prague, Czech Republic. P928.
16. Endermann, R. C. H. Ladel, H. Broetz-Oesterhelt, and H. Labischinski. 2004. BAY 73-7388, a novel aminomethylcycline, is highly active in vivo in a murine model of pneumococcal pneumonia. 14th European Congress of Clinical Microbiology and Infectious Diseases. Prague, Czech Republic. P931.
17. George, A. M.,, and S. B. Levy. 1983. Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics in Escherichia coli: Involvement of a non-plasmid-determined efflux of tetracycline. J. Bacteriol. 155:531540.
18. George, A. M.,, and S. B. Levy. 1983. Gene in the major co-transduction gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics. J. Bacteriol. 155:541548.
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20. Ladel, C.H.,, R. Endermann,, H. Broetz-Oesterhelt,, and H. Labischinski. 2004. BAY 73-7388 demonstrates greater activity than linezolid in a range of murine models of skin and soft tissue infection. 14th European Congress of Clinical Microbiology and Infectious Diseases. Prague, Czech Republic. P929.
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22. Levy, S. B.,, and L. McMurry. 1978. Plasmid-mediated resistance involves alternative transport systems for tetracycline. Nature. 276:9092.
23. Levy, S. B.,, L. M. McMurry,, V. Burdett,, P. Courvalin,, W. Hillen,, M. C. Roberts,, and D. E. Taylor. 1989. Nomenclature for tetracycline resistance determinants. Antimicrob. Agents Chemother. 33:13731374.
24. Levy, S. B.,, L. M. McMurry,, T. M. Barbosa,, V. Burdett,, P. Courvalin,, W. Hillen,, M. C. Roberts,, J. I. Rood,, and D. E. Taylor. 1999. Nomenclature for new tetracycline resistance determinants. Antimicrob. Agents Chemother. 43:15231524.
25. Macone, A.,, J. Donatelli,, T. Dumont,, S. B. Levy,, and S. K. Tanaka. 2003. In vitro activity of PTK 0796 against Grampositive and Gram-negative organisms. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Abst. 2439.
26. Martell, M. J., Ross, A. S., and J. H. Boothe. 1967. The 6-Deoxytetracyclines. IX. Imidomethylation. J. Med. Chem. 10:485486.
27. McKenney, D.,, J. M. Quinn,, C. L. Jackson,, J. L. Guilmet,, J. A. Landry,, S. K. Tanaka,, and E. P. Cannon. 2004. BAY 73-7388, a novel aminomethylcycline, exhibits potent efficacy in pulmonary murine models of infection. 14th European Congress of Clinical Microbiology and Infectious Diseases. Prague, Czech Republic. P927.
28. McKenney, D.,, J. M. Quinn,, C. L. Jackson,, J. L. Guilmet,, J. A. Landry,, S. K. Tanaka,, and E. P. Cannon. 2003. Evaluation of PTK 0796 in experimental models of infections caused by Gram-positive and Gram-negative pathogens. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Abst. 2627.
29. McKenney, D.,, J. M. Quinn,, C. L. Jackson,, J. L. Guilmet,, J. A. Landry,, S. K. Tanaka,, and E. P. Cannon. 2003. The efficacy of PTK 0796 in murine models of Streptococcus pneumoniae infections. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Abst. 2637.
30. McMurry, L., Petrucci, R., and S. B. Levy. 1980. Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in E. coli. Proc. Natl. Acad. Sci. USA 77:39743977.
31. McMurry, L. M.,, and S. B. Levy,. 2000. Tetracycline resistance in gram-positive bacteria. p. 660677. In V. A. Fischetti,, R. P. Novick,, J. J. Ferretti,, D. A. Portnoy,, and J. I. Rood (ed.), Gram-Positive Pathogens. American Society for Microbiology, Washington, D.C.
32. McNicholas, P.,, M. McGlynn,, G. G. Guay,, and D. M. Rothstein. 1995. Genetic analysis suggests functional interactions between the N- and C-terminal domains of the TetA(C) efflux pump encoded by pBR322. J. Bacteriol. 177:53555357.
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38. Nelson, M. L.,, M. Y. Ismail,, L. McIntyre,, B. Bhatia,, P. Viski,, G. Rennie,, D. Andorsky,, D. Messersmith,, K. Stapleton,, J. Dumornay,, P. Sheahan,, A. K. Verma,, T. Warchol,, and S. B. Levy. 2003. Versatile and facile synthesis of diverse semi synthetic tetracycline derivatives via Pd-catalyzed reactions. J. Org. Chem. 68:58385851.
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Tables

Generic image for table
Table 1.

In vitro activity of PTK 0796 ( )

NA, not applicable. Not clinically useful.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 2.

Mechanism of action of PTK 0796 versus RN450 ( )

IC50, concentration of compound that inhibits by 50% the incorporation of radiolabelled precursors into TCA precipitable material following incubation of mid-log cultures of RN450.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 3.

Inhibition of protein synthesis in resistant to tetracycline

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 4.

Pharmacokinetics of a single dose (10 mg/kg) of PTK 0796 ( )

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 5.

Tissue pharmacokinetics (rat) of PTK 0796 ( )

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 6.

Protein binding of PTK 0796( )

Plasma samples spiked at indicated concentrations and extent of binding in microequilibrium dialysis determined by LC-MS/MS.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 7.

Stability of PTK 0796 in liver microsomes ( )

Liver microsome samples with 25 μM compound, incubated at 37°C for 60 min and unchanged compound remaining in reactions determined by LC-MS/MS.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 8.

Efficacy of PTK 0796 in murine models of systemic infections ( )

Infections were lethal in untreated controls. Efficacy (dose protective of 50% of animals) was determined on the basis of survival 7 days after infection.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40
Generic image for table
Table 9.

Efficacy of PTK 0796 in murine tissue-based models of infection ( )

Efficacy (ED) based on mean 100-fold reduction in viable bacteria per gram of tissue 22 h after treatment.

Citation: Nelson M, Tanaka S. 2005. From Perplexing Proteins to Paratek Pharmaceuticals: One Scientific Front Forged by Stuart B. Levy, p 537-549. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch40

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