GLYCOPEPTIDES : how can a structural modification bring to a new life an old family of antibiotics?

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1 GLYCPEPTIDES : how can a structural modification bring to a new life an old family of antibiotics? F. Van Bambeke Pharmacologie cellulaire et moléculaire Université catholique de Louvain Brussels - Belgium

2 drug drug drug drug drug drug pharmacodynamics pharmacokinetics drug drug drug drug drug drug drug drug drug drug drug physico-chemistry drug design drug drug drug drug drug

Glycopeptide story: from natural to semi-synthetic synthetic derivatives ~ 1950 : discovery of vancomycin in Mississipi mud ~ 1985 : large clinical use in USA Gram(+) infections and digestive tract

3 Glycopeptide story: from natural to semi-synthetic synthetic derivatives ~ 1950 : discovery of vancomycin in Mississipi mud ~ 1985 : large clinical use in USA Gram(+) infections and digestive tract decontamination Problems: toxicity of vancomycin due to impurities better purification procedures (after 1970 ) emergence of resistance. By the way.~ 1980 : discovery of teicoplanin, as a natural GP with improved PK largely used in Europe

4 Glycopeptide story: from natural to semi-synthetic synthetic derivatives ~ 1990 : Launching of large scale research program for finding GP with optimized properties hemi-synthetic compounds Malabarba and icas Med Res Rev. (1997) 17:69-137; Curr Med Chem. (2001) 8: vancomycin teicoplanin oritavancin telavancin dalbavancin (1996) (2001) (2004) phase II / III (1999)

5 Peptidoglycan synthesis reticulation cell wall D-ala cytosol precursor synthesis

6 Glycopeptide mechanism of action binding to D-Ala-D-Ala prevents the reticulation of peptidoglycan precursors

7 But resistance came c in...

8 Resistance in enterococci large clinical use in USA started in ~ 1985 Bonten et al, Lancet ID (2001) 1:

9 Resistance in enterococci glycopeptide binding to depsipeptide D-Lac, D-Ser P. Courvalin et al s work

10 Resistance in enterococci from susceptible to resistant Arthur et al, Trends Microbiol (1996) 4: hydrogen bound is missing!

11 Resistance in staphylococci (GISA) AB AMP VA GE RIF LVX TET SMX Q-D LZD MIC

12 Resistance in staphylococci (GISA) multiplication of the target! tickened Cell wall iramatsu Lancet ID (2001) 1: Cui et al J in Microbiol (2003) 41:5-14

13 Resistance in staphylococci (GRSA) AB VA TEC MIC 32 4

14 Current glycopeptides: what do they offer to us? parameter spectrum vanco - teico Gram (+) & MRSA but VRE GI/RSA PD PK static or slowly bactericidal t ½ short for vanco safety (red-man syndrome) oto-& nephrotoxicity

15 Glycopeptides: how can we improve? parameter spectrum vanco - teico Gram (+) & MRSA but VRE GI/RSA ideal glycopeptide Gram (+) & MRSA, GI/RSA, VRE PD PK safety static or slowly bactericidal t ½ short for vanco (red-man syndrome) oto-& nephrotoxicity quickly, conc. dependent bactericidal t ½ diffusibility (CS) side effects

16 Glycopeptides: how can we improve?

17 Glycopeptides: how can we improve? 2 3 C C 3 C C 2 C 3

18 Glycopeptide updated mechanism of action dimerization and / or membrane anchoring activity

19 Glycopeptide updated mechanism of action in VRE efficient binding still possible!

20 Glycopeptides: how can we improve? 2 3 C C 3 C C 2 C 3 binding to D-Ala-D-Ala

21 Glycopeptides: how can we improve? 2 3 C C 3 dimerization C C 2 C 3 binding to D-Ala-D-Ala

22 Glycopeptides: how can we improve? 2 3 C C 3 membrane anchoring, transglycosylase inhibition dimerization C C 2 C 3 binding to D-Ala-D-Ala

23 Molecules in clinical development: DESIG

24 From vancomycin to oritavancin 2 3 C C 3 C C 2 C 3

25 From vancomycin to oritavancin epi-vancosamine 2 3 C C 3 C C 2 C 3

26 From vancomycin to oritavancin 4-epi-vancosamine self-association capacity C C 3 3 C C 3 C C 2 C 3 LY264626

27 From vancomycin to oritavancin lipophilic side chain activity including against resistant enterococci 2 3 C C 3 3 C C 3 C C 2 C 3 Cooper et al (1996) J Antibiot 49:

28 From vancomycin to telavancin 2 3 C C 3 C C 2 C 3

29 From vancomycin to telavancin chain length offering balanced activity against MRSA & resistant enterococci 3 C C C 3 C 2 C 3

30 From vancomycin to telavancin 3 C C 3 C C 2 C 3 Leadbetter et al (2004) J Antibiot 57: P 3 2 compensates the effect on the lipophilic side chain on half-life

31 From teicoplanin to dalbavancin C A c 2 C

32 From teicoplanin to dalbavancin C A c C 3 C

33 From teicoplanin to dalbavancin removal of -acetylglucosamine activity (against resistant enterococci) C C 3 C A40926

34 From teicoplanin to dalbavancin C activity C 3 - C Malabarba & Ciabatti (2001) Curr Med Chem 8:

35 ew glycopeptides are more cationic and amphiphilic than vancomycin

36 ew glycopeptides are more cationic and amphiphilic than vancomycin ew chemical entities ew mode of action and new pharmacodynamic properties ew pharmacokinetic profile But also. new potential side effects

37 ew glycopeptides: new mode of action and pharmacodynamic properties

38 Spectrum of activity strain resist. vanco orita tela teico dalba enterococci susc. VanA VanB 1-2 > > >128 1 S. aureus Methi-S < 0.5 Methi-R GISA GRSA > Candiani et al., J.Antimicrob.Chemother. (1999) 44: Judice & Pace, Bioorg.Med Chem.Lett. (2003) 13: King et al., J Antimicrob.Chemother. (2004) 53: Streit et al., Diagn.Microbiol.Infect.Dis. (2004) 48:

39 Spectrum of activity strain resist. vanco orita tela teico dalba enterococci susc. VanA VanB 1-2 > > >128 1 S. aureus Methi-S < 0.5 Methi-R GISA GRSA > activity against strains resistant to vancomycin

40 Barcia-Macay et al. Unpublished Pharmacodynamic properties slowly cidal effect conc. dependent, bactericidal effect 4 vancomycin oritavancin telavancin control 1 X MIC 10 X MIC 40 X MIC log CFU from time time (h) time (h) time (h)

41 iggins et al., ICAAC (2004) Alteration of membrane integrity

42 ew glycopeptides: new pharmacokinetic profile

43 Pharmacokinetic properties in humans parameter Vanco rita Tela Teico Dalba (15 mg/kg) (3 mg/kg) (7.5 mg/kg) (6 mg/kg) (15 mg/kg) peak (mg/l) through (mg/l) < 5 40 (24 h) (24 h) (24 h) (168 h) protein binding % 90 % 90-93% 90 % 98 % terminal t½ (h) h Intermune, Inc, data on file Barriere et al, ICAAC 2003 Steiert & Schmitz, Curr.pin.Investig.Drugs (2002) 3: once-a-day administration once-a-week administration

44 Van Bambeke et al. AAC (2004) 48: Cellular pharmacokinetics J774 macrophages; extracellular concentration: 25 mg/l; 24 h

45 Comparison with other antibiotics J774 macrophages; extracellular concentration: 25 mg/l; 24 h cellular / extracellular concentration ratio oritavancin vancomycin azithromycin

46 Mechanism of cellular accumulation chloroquine azithromycin RP latex beads

47 Van Bambeke et al. AAC (2004) 48: Mechanism of cellular accumulation Uptake linear over 4 h as for markers of endocytosis Rate of uptake similar to that of a marker of adsorptive endocytosis

48 Subcellular localization Subcellular localization MARKERS F : lysosomes mitochondria membranes

49 ew glycopeptides: cellular pharmacokinetics cellular pharmacodynamics

50 PK/PD properties of oritavancin in a model of S.aureus infected macrophages CFU / mg prot 10 7 VA RI control 0.25 µg/ml 2.5 µg/ml 50 µg/ml 10 µg/ml Time (h) 25 µg/ml Seral et al AAC (2003) 47 :

51 Barcia-Macay et al. Unpublished PK/PD properties of oritavancin in a model of S.aureus infected macrophages (X MIC)

52 ritavancin is the most active antibiotic against intracellular S. aureus among those tested so far!

53 oritavancin control Intracellular bactericidal activity is visible!

54 ew glycopeptides: I VIV DATA animal models Combined extra-and intracellular activity recurrent infections, including by resistant organisms

55 efficacy shown in. pouch meningitis catheter endocarditis Combined extra-and intracellular activity recurrent infections, including by resistant organisms

56 ew glycopeptides: I VIV DATA clinical studies Combined extra-and intracellular activity recurrent infections, including by resistant organisms

57 inical experience complicated skin and skin structure infection caused by Gram (+) including MRSA (phase II/III; double blind, randomized) 517 pts SUCCESS : bacteriological Vancomycin 15 mg/kg bid 3-7days followed by oral cephalexin days 76 % ritavancin mg/kg qd 3-7 days 74 % clinical with MRSA 80 % 80 % = 76 % 74 % Wasilewski et al. ICAAC (2001)

58 Stryjewski et al. IDSA meeting (2004) inical experience complicated skin and skin structure infection caused by Gram (+) including MRSA (phase II; double blind, randomized) 167 pts vancomycin / penicillin telavancin SUCCESS : bacteriological 74 % 84 % clinical with MRSA 77 % 69 % = < 80 % 82 %

59 inical experience complicated skin and skin structure infection caused by Gram (+) including MRSA (phase II; controlled, randomized) 62 pts Vancomycin, ceftriaxone, cefazolin or clindamycin for 7-21 days Dalbavancin 15 mg/kg day mg/kg day 8 SUCCESS : bacteriological clinical 64 % 76 % 73 % 94 % Selzer et al. in Infect Dis (2003) 37:

60 ew glycopeptides: cellular pharmacokinetics cellular toxicity?

61 Van Bambeke et al. submitted Microscopic examination of oritavancin treated cells macrophages fibroblasts

62 Microscopic examination of oritavancin treated cells fibroblasts

63 Lipid accumulation: concentration-effect effect relationships

64 Lipid accumulation: time effect and reversibility

65 Lipid accumulation: correlations

66 Safety profile in humans o major side effect in clinical trials, BUT small number of patients appropriate techniques should be used to detect cellular alterations.

67 how can a structural modification bring to a new life an old family of antibiotics? lipophilic side chain new mode of action activity against resistant strains bactericidal, conc.-dependent effect ideal PD profile new pharmacokinetic profile prolonged half-life/high prot. binding high cell accumulation/intracell. activity infrequent administrations recurrent infections 2 3 C C C 3 C 2 C 3 new toxic effects in vitro thesaurismosis safety issues?????

68 Glycopeptides: have we improved? parameter spectrum vanco - teico Gram (+) & MRSA but VRE - GISA new glycopeptides Gram (+) & MRSA, GISA, VRE PD PK safety static or slowly bactericidal t ½ short for vanco (red-man syndrome) oto-& nephrotoxicity quickly, conc. dependent bactericidal t ½ diffusibility (CS) side effects

69 Thanks to 3 C 2 C 3 C 3 C C 3 Maritza Barcia-Macay Stéphane Carryn ugues Chanteux Cristina Seral Donatienne Tyteca Marie-Paule Mingeot-Leclercq Paul M. Tulkens C 2 C 3 Francine, Marie-aire, ancy

Activity of antibiotics against intracellular S. aureus

Activity of antibiotics against intracellular S. aureus F. Van Bambeke Unité de Pharmacologie cellulaire et moléculaire Université catholique de Louvain Brussels, Belgium Disclosures Grants-in-aid from