antimicrobials in animal health – lessons from nature frank … · 2012-10-25 · session 1...
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Session 1Alternatives to Antibiotics: Lessons from Nature
Antimicrobials in animal health –Lessons from nature
Frank BlechaKansas State UniversityKansas State University
Manhattan, Kansas
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Alternatives to AntibioticsBegin at the End
• Is there a need?
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OO is for OutbreakWhen a drug-resistantsalmonella struck a Vermontfarm health officials knew itfarm, health officials knew itmight be just the beginning
Troubled paradise U S News& WORLD REPORT
Troubled paradise U.S.NewsNovember 24, 1997
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Alternatives to AntibioticsBegin at the End
• Is there a need?• Does it work?• Is it cost effective?• Is it cost effective?• Will it be accepted?
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Host Defense Against MicrobesHost Defense Against Microbes
Cells Physical barriers
Molecules Antimicrobial peptides
Adapted from Ganz T, 2003
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Wh t A ti i bi l P tid ?PMNs
What are Antimicrobial Peptides?PMNs
Neutrophils
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Host Defense Against MicrobesHost Defense Against MicrobesAntimicrobial peptides:Antimicrobial peptides:
PMN
Neutrophils
Bainton, 1992
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AMP Classification
DefensinsCathelicidinsalpha
DefensinsCathelicidinsp
betathetatheta
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Cathelicidins EXON 1 EXON 2 EXON 3 EXON 4
PRE PRO (Cathelin) MATURE PEPTIDE3’-UTR5’-UTR
29-30 aa 94-114 aa 12-79 aa
Porcine Bovine Ovine Lapine Human Equine MurinePR-39 Bac-5 SMAP-29 CAP-18 LL-37/ eCATH 1-3 CRAMPPG 1-5 Bac-7 Bac-7.5 p-15s hCAP-18PF 1 2 BMAP D d tidPF 1-2 BMAPs DodecapeptidePMAPs Indolicidin Dodecapeptide
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Beta DefensinsEXON 1 INTRON EXON 2
PRE PRO MATURE PEPTIDE5’-UTR
PRE PRO MATURE PEPTIDE3’-UTR20-29 aa 2-8 aa 36-42 aa
Porcine Bovine Avian Murine Ovine Caprine Human
pBD-1 TAP GAL 1-2 mBD 1-6 sBD 1-2 gBD 1-2 hBD 1-4LAP THP 1-2 rBD 1-2
Porcine Bovine Avian Murine Ovine Caprine HumanpBD-1 TAP GAL 1-2 mBD 1-6 sBD 1-2 gBD 1-2 hBD 1-4
LAP THP 1-2 rBD 1-2 EBDBNBD 1-13 EBDBNBD 1-13
Sang et al., Mamm. Genome, 2006, 17:332
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Why AMPs?y• Potential for novel antimicrobials • Active against a broad spectrum of microbesg p• Difficult for microbes to develop resistance
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AMP Mechanism of Action1 2
AMP Mechanism of Action 1
DNA ProteinRNA4
2
3
DNA ProteinRNATranscription Translation
3
Adapted from Radek and Gallo, Semin Immunopathol 2007, 29:27-43
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AMP or Host Defense Peptide
AMP
HDP
Modified from Gallo and Nizet, Curr Allergy Asthma Rep. 2003, 3:402-9.
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In Vivo Activity?y
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HD6 nanonets confer mucosal immunity
Ouellette and Selsted, Science 2012;337:420-421
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Lessons from the Pigg
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PR-39, an Amphipathic Peptide
RRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPPRFPPRFPRRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPPRFPPRFP
Proline = 48 7% Arginine = 25 6%
Basic, Neutral Polar, Nonpolar
Proline = 48.7% Arginine = 25.6%
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Minimal Inhibitory and BactericidalMinimal Inhibitory and Bactericidal Concentrations of PR-39 & PR-26
Shi et al., Antimicrobial Agents Chemotherapy 1996, 40:115-121
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Inhibition of Salmonella Typhimurium Invasion
30
yp
20x100
0)
20
acte
ria (x
180120
me (min)
10
Viab
le b
a
12060
305
cubati
on tim
e
ControlPR-39
PR-26
0
IncuShi et al., Antimicrobial Agents Chemotherapy 1996, 40:115-121
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Increased Resistance to Salmonella TyphimuriumSalmonella Typhimurium
100
80
)
60
viva
l (%
50 µg PR-26
20
40
Surv 100 µg PR-26
Control
0 3 6 9 12 1500 3 6 9 12 15
Day postchallangeShi et al., Antimicrobial Agents Chemotherapy 1996, 40:115-121
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pBD-1 Protects against B. pertusisTreated with pBD-1 Non-treated
eal
leng
ePo
st C
ha 4
Day
s P
Elahi et al., Infect Immun 74:2338, 2006
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Bacterial Resistance to AMP?Bacterial Resistance to AMP?
51 54
1
2 32 3
Adapted from Radek and Gallo, Semin Immunopathol 2007, 29:27-43
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Alternatives to AntibioticsBegin at the End
• Is there a need?+/ • Does it work?
• Is it cost effective?+/-? • Is it cost effective?
• Will it be accepted?+?
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Acknowledgments
UCLABob LehrerYongming Sang
K-State
Piotr RuchalaChris RossBob RowlandDanielle GoodbandDanielle Goodband
USDA & NIHUS &
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Thank You