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What future for antibiotics?

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Accounted for 70% of deaths in birthing mothers. Typhus ... ampicillin. Escherichia coli. 12,000. ceftazidime. Pseudomonas aeruginosa. 26,000. vancomycin ... – PowerPoint PPT presentation

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Title: What future for antibiotics?


1
What future for antibiotics?
  • Anthony W. Smith, BPharm, PhD, MRPharmS
  • Dean

2
The pre-antimicrobial era
  • Black death in 14th and 15th centuries
  • European population halved
  • Puerperal (streptococcal) sepsis
  • Accounted for 70 of deaths in birthing mothers
  • Typhus
  • Napolean Bonapartes army reduced from 665,000 to
    93,000. Returners infected and killed 2,000,000
  • Influenza
  • 1918 19 pandemic killed 30,000,000 in Europe,
    Asia, Australia and the Americas
  • TB
  • One of the biggest killers of mankind 1,750,000
    killed in 2003

3
Milestones in antimicrobial chemotherapy
  • 1929 Fleming discovers penicillin
  • 1935 Gerhard Domagk develops sulphonamides
  • 1939 Discovery and purification of gramicidin by
    René Dubos
  • 1941 USA commences commercial production of
    penicillin
  • 1945 The golden age of antibiotics begins with
    the introduction of cephalosporins,
    chloramphenicol, tetracyclines, erythromycin,
    vancomycin, gentamicin and many variations on the
    penicillin (b-lactam) nucleus

4
Milestones in antimicrobial chemotherapy
  • 1953 Multi-drug-resistant dysentery bacilli in
    Japan. Drug-resistant TB
  • 1960 Methicillin-resistant S. aureus
  • 1980s Major drug companies scale-down antibiotic
    discovery programmes
  • 2000 Linezolid launched first new class of
    agents in 30 years

5
Impact on the health of nations
One hundred years ago, the three major causes of
death in the United States were tuberculosis,
pneumonia and gastrointestinal infections all
forms of bacterial infections.by the end of the
20th century, only lower respiratory tract
infections still ranked amongst the top ten
causes of death. US Senate briefing paper,
2002.
6
World Health
7
GLOBAL INFECTIOUS DISEASE STATISTICS (Sep 04)
DISEASE POPULATIONS AT RISK NEW CASES/YEAR WORLDWIDE DEATHS/YEAR WORLDWIDE
HIV/AIDS Men, women and children worldwide 5 million 3 million
MALARIA Prominent in developing countries, especially in Africa 300-500 million 1.5 - 2.7 million
TUBERCULOSIS Men, women and children worldwide 10-15 million 2 million
AFRICAN SLEEPING SICKNESS (AFRICAN TRYPANOSOMASIS) 36 countries of Sub-Saharan Africa 300,000 - 500,000 66,000
CHAGAS DISEASE (AMERICAN TRYPANOSOMASIS) ¼ of all people in Central and South America 16 - 18 million 50,000
8
Antibiotic targets
  • Peptidoglycan synthesis
  • Beta-lactams, glycopeptides
  • RNA polymerase
  • Protein synthesis
  • Aminoglycosides, tetracyclines, macrolides,
    oxazolidinones,
  • Nucleic acid synthesis
  • Fluoroquinolones

9
Beta-lactams and glycopeptides inhibit
peptidoglycan synthesis
NAG
NAM
Glycopeptides Bind terminal D-Ala-D-Ala Prevent
subunit incorporation
NAG
NAG
NAM
NAM
NAG
NAM
Beta-Lactams Bind PBPs Prevent trans and
carboxypeptidation
10
b-Lactams - mode of action
D-Ala-D-Ala
11
that we had essentially defeated infectious
diseases and could close the book on them US
Surgeon General, William H. Stewart 1969
12
Is the emergence of antibiotic resistance
inevitable?

Natural selection makes antibiotic resistance
inevitable, rendering any antibiotic less
profitable over time the situation is
exacerbated by the overuse and misuse of
currently available antibiotics. Stephen J.
Projan, 43rd ICAAC, Chicago 2003
13
Emergence of antibiotic resistance by selective
pressure
  • EDG Murray (1917 1954) strain collection
  • pre-antibiotic era isolates of enteric bacteria
    practically fully sensitive to a range of
    antibiotics
  • 2/433 penicillin resistant
  • 9/433 tetracycline resistant
  • Rapid emergence of resistance of the past 60
    years
  • Mutation
  • Genetic re-arrangement
  • Genetic resistance determinants
  • Resistance genes can be spread by horizontal
    transfer

14
Hospital-acquired infections to drug-resistant
bacteria (USA 2002)
Pathogen Antibiotic Estimated cases
Staphylococcus aureus methicillin 102,000
Coag ve staphylococci methicillin 130,000
Enterococci vancomycin 26,000
Pseudomonas aeruginosa ceftazidime 12,000
Escherichia coli ampicillin 65,000
Pseudomonas aeruginosa imipenem 16,000
Klebsiella pneumoniae ceftazidime 11,000
15
Evolution of antibiotic resistance in
Staphylococcus aureus
oxacillin, flucloxacillin
vancomycin teicoplanin
penicillin
methicillin
Penicillin resistance
methicillin resistance
Epidemic strains
1990
2000
2002
1980
1996
1960
1970
1950
1940
GISA
gentamicin- resistant MRSA
MRSA
VRSA
16
MRSA in Europe (2002 data)
  • Greece 48.6
  • UK 44.5
  • Germany 27.2
  • Spain 23.5
  • Belgium 19.2
  • Czech Republic 6.2
  • Netherlands 1.0
  • Sweden 0.7

Source European Antimicrobial Resistance
Surveillance System
17
Antibiotics mechanisms of resistance
  • Alteration in target site
  • Alteration in access to the target site
  • Production of inactivating enzymes

18
Resistance to antibacterial agents
Mechanism of resistance
19
b-lactam antibiotics andb-lactamase
  • Chromosomal b-lactamase
  • inducible
  • Staphylococcus aureus, some Gram-negatives
    including Pseudomonas sp. and Enterobacteriacae
  • Plasmid-mediated b-lactamase
  • constitutive
  • TEM type most common, also extended spectrum

20
Charge stabilisation by positively-charged lysine
and arginine residues
Lactam attack by serine residue
21
b-lactamase inhibitors
Clavulanic acid
Sulbactam
Tazobactam
22
Altered penicillin-binding proteins (PBPs)
  • transpeptidases and carboxypeptidases required
    for cross-linking and pruning of peptidoglycan
    (PG).
  • PG synthesis has to be carefully regulated to
    avoid over extensive cross-linking
  • PBP2a methicillin resistance in S. aureus

23
Glycopeptides block carboxypeptidase/transpeptidas
e
24
Glycopeptide resistance
Stable complex with 5 hydrogen bonds inhibits
transpeptidation
Unstable complex with 4 hydrogen bonds
25
Glycopeptide resistance
26
Resistance by efflux pumps
  • Antibiotics pumped out of cell
  • can explain resistance to structurally unrelated
    agents eg tetracyclines and quinolones

Tetracycline transported into cell
Tetracycline pumped out of cell
Drug does not reach optimum concentration
27
Efficacious clinical introductions need to keep
pace with the erosion of the current
antibacterial armamentarium
28
Keeping up with resistance?
29
The search for new agents
30
Are there more targets for antibiotics?
  • Metabolic enzymes are attractive targets
  • Central role in microbial physiology
  • High conservation among various pathogens
  • Enzyme assays suitable for high through-put
    screening
  • Numerous targets must exist?

31
The promise of omics?
  • Genomic approach
  • Gene-by gene strategies to identify those
    essential for in vivo growth

32
Search in Salmonella
  • Phenotypes of metabolic mutants in vivo
  • Essential, contributing and dispensable
  • In vivo proteomics
  • Recover Salmonella from caecum or spleen
  • Identify expressed proteins by mass spec

Nature (2006) 440,303-307
33
Shortage of new targets
  • 155 promising target candidates
  • 64 conserved in diverse set of major human
    pathogens S. aureus, E. faecalis, S. pneumoniae
    and H. influenzae
  • Almost all belong to pathways already exploited
    by antibiotics
  • 8 new candidates have very high sequence
    identities with human enzymes
  • Toxicity

Nature (2006) 440,303-307
34
RNA interference
  • Knock-down technology
  • Shot-gun clone into inducible anti-sense
    expression vector
  • Replica plate and examine for growth or no growth
    under inducing conditions
  • Fatty acid biosynthesis inhibition (Merck)
  • Lipid A biosynthesis (Chiron/Novartis)
  • Novel ribosomal sites (Pleuromutilins/GSK)

35
Platensimycin and fatty acid biosynthesis
  • Produced by Streptomyces platensis
  • Identified from a screen of 250,000 extracts from
    drug-producing micro-organisms
  • Only third new class of molecule (linezolid and
    daptomycin) in 40 years

Nature (2006) 441,293-294
36
Platensimycin and fatty acid biosynthesis
Nature (2006) 441,293-294
37
Enzybiotics
  • Phage-coded lysins that destroy the cell wall

38
Modify but dont kill a novel approach?
  • Introduction of new antibiotic invariably leads
    to selection of resistant forms
  • Rather than kill, why not disable it, reducing
    its ability to survive within the host?
  • Modify the phenotype
  • Virulence, fitness, qs, tolerance and biofilm

39
Bacteria are only opportunistic invaders of
tissues already weakened by crumbling defences
René Dubos, 1955

40
Modification of phenotype reducing fitness
  • The modulation of the antibiotic resistance and
    the virulence profile of methicillin resistant
    Staphylococcus aureus (MRSA) using products
    derived from green tea

41
Components of Japanese green tea modify
resistance to key antibiotics
TEA
Aqueous extracts of Camellia sinensis, as well as
purified catechin gallates, convert MRSA strains
to the methicillin susceptible phenotype
Yam TS, Hamilton-Miller JMT Shah S,
1998 Stapleton PD, Shah S, Anderson JC, Hara Y,
Hamilton-Miller JMT Taylor PW, 2004
42
Activity of catechins in combination with
oxacillin EMRSA-16
oxacillin breakpoint
(-)-epigallocatechin
(-)-epicatechin gallate
(-)-epicatechin
(-)-epigallocatechin gallate
0.5
1
2
4
8
16
32
64
128
256
512
Oxacillin MIC (mg/L) in combination with
catechins (6.25-25 mg/L)
Stapleton PD, Shah S, Anderson JC, Hara Y,
Hamilton-Miller JMT Taylor PW, 2004
43
Antibiotics in 2006
  • A role for screening against compound libraries,
    particularly natural products
  • Maintain the activity of existing agents
  • Rational prescribing
  • Completing courses of treatment
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