strategies to design new antibacterial drugs · antimicrobial agent which circumvents antibacterial...
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Jordi Vila Department of Clinical Microbiology Hospital Clinic, Barcelona
Strategies to design new antibacterial drugs
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Boucher HW, et al. Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America
Clinical Infectious Diseases 2009; 48:1–12
1983-1987
1988-1992
1993-1997
1998-2002
2003-2007
2008-2012
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter baumannii
Pseudomonas aeruginosa
Enterobacter spp
Dramatic decrease in the
DEVELOPMENT of new
ANTIBACTERIAL AGENTS
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bacteria
1. Derivative of known antibacterial agents
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• Modification of the basic structure of the
antimicrobial agent which circumvents
antibacterial resistant mechanisms
Derivative of known antimicrobial agents
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• Modification of the basic structure of the
antimicrobial agent which circumvents
antibacterial resistant mechanisms
Derivative of known antimicrobial agents
• Development of a compound inhibiting
the mechanisms of resistance for an
antibacterial agent
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Blocking antibacterial resistance mechanisms
- Inhibition of beta-lactamases
- Inhibition of efflux pumps
- Inhibition of aminoglycoside-modifying enzymes
- Blocking the SOS response
Derivative of known antimicrobial agents
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new inhibitors
- Inhibition of beta-lactamases
A B C D
Clavulanic acid, tazobactam, sulbactam
carbapenemases
AmpC
carbapenemasas
Derivative of known antimicrobial agents
Blocking antibacterial resistance mechanisms
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Blocking antibacterial resistance mechanisms
- Inhibition of beta-lactamases
- Inhibition of efflux pumps
- Inhibition of aminoglycoside-modifying enzymes
- Blocking the SOS response
Derivative of known antimicrobial agents
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Vila J, Fàbrega A, Roca I, Hernández A, Martínez JL
Efflux pumps as an important mechanism for quinolone resistance
Adv Enzymol Relat Areas Mol Biol 2011: 77; 167-235
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Vila J, Fàbrega A, Roca I, Hernández A, Martínez JL
Efflux pumps as an important mechanism for quinolone resistance
Adv Enzymol Relat Areas Mol Biol 2011: 77; 167-235
Efflux pump of the RND family found in Enterobacteriaceae Porin of
the outer membrane
Protein of fusion
Efflux pump
Efflux pump inhibitor RND (Preclinical phase)
MP-601,205
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bacteria
2. New antibacterial agents 1. Derivative of known antibacterial agents
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• Classical or whole-cell antibacterial assay
• Secondary metabolites of bacteria and fungi with
antimicrobial activity
• Plant extracts
• Marine macro and microorganisms
• Ex: Deep-sea sediment sampling yielded an
actinomycete which produces the abyssomicins
• Uncultured bacteria
DISCOVERY OF NEW ANTIBACTERIAL AGENT
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• Genomic or target-based antibiotic discovery
– New tools on chemistry and molecular biology
• Genomics and recombinant DNA.
• Molecular modeling
• Combinatorial chemistry and chemical structure.
DISCOVERY OF NEW ANTIBACTERIAL AGENT
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Pharma. Indust. Antibacterial agent
Inhibitors of new protein targets
“Target”
Pharmacia / Pfizer
GlaxoSmithKline /
Affinium
BRX-1555
API-1252 Biosynthesis of fatty acids (FabI)
platensimicina Merck
QPT-1 B subunit of topoisomerase II
GSK-322 peptidil deformilase GlaxoSmithKIine
ACHN-971 Achaogen Synthesis of lipopolisacharide
Bacterial “riboswitch” BioRelix
VRT-752586 ATPase domain of GyrB / ParE Pfizer / Vertex
Biosynthesis of fatty acids (FabI)
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bacteria 3. Blockers of virulence factors
2. New antibacterial agents 1. Derivative of known antibacterial agents
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Antivirulence drugs: A therapeutic alternative?
• In the presence of these compounds, bacterial pathogens will
have difficulties to generate an infection and will therefore be
more easily eliminated by immune systems
• Proposed targets for antivirulence drugs:
– Fimbria (GNB), Surface proteins (GPB)
– Toxins
– Type III secretion systems
– Quorum sensing
– Regulation of virulence factors:
• Two component systems; e.i: Enterococcus, the vanA gene is regulated by vanR-vanS
• Monoclonal antibodies
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Vaccines and immunoglobulins with activity against S. aureus
Aurexis Monoclonal Ab (tefibazumab) against clumping factor A
No benefit versus placebo
Sthap VAX Conjugated vaccine Failure in phase III
Altastaph Policlonal immunoglobulin hyperimmune
Stop development
Aurograb Monoclonal Ab against S. aureus
Failure in phase II
Chimeric monoclonal Ab against lipoteicoic acid
Pagibaximab fase II-III
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Panobacumab Monoclonal against P aeruginosa phase II-III
KB-001 Monoclonal against P aeruginosa phase II
Raxibacumab Monoclonal against Ag Toxin of B. anthracis
phase III
Valortim (MDX-1303) phase I Bacillus anthracis
Anthim (ETI-204) phase I Bacillus anthracis
Monoclonal antibodies
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bacteria 3. Blockers of virulence factors
4. Nanoparticles and Antibacterial peptides /
peptidomimetics
2. New antibacterial agents 1. Derivative of known antibacterial agents
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NANOBIOCIDES
• Metal and metal oxides e.g. nAg, ZnO, Cuo, TiO2
• Engineered/synthesized nanoparticules such as
fullerenes, e.g. nanomagnetite (nC60) and carbon
nanotuves
• Natural antimicrobial substances e.g.
antimicrobial peptides and chitosan
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Antibacterial peptides (ABPs)
• ABPs are ancient members of the innate defense
systems
• Flexible and approachable nature of peptide-synthesis
chemistries has given rise to an explosion in the
number of rationally designed synthetic examples
• May show high toxicity and low stability
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Antibacterial agent
Antibacterial peptides in phase III and II clinical trials
Description Indication
Omiganan Indolicidin
Isegana Protegrin
Topical, anti-acne
Locilex Pexiganan Topical, diabetic food
PAC-113 Histatin
LTX-109 Synthetic mimetic
Failed
DPK-060
PMX-30067
Topical, mucositis
Topical, MRSA
Topical, atopical dermatitis
Intravenous, MRSA
LL37-variant
Defensin core mimetic
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Protein epitope mimetics
• Fully synthetic, cyclic, peptide-like, medium size
molecules
• Ability to mimic secondary protein strcutures such as
the b-hairpin allows them to interfere with protein-
protein interactions.
PEM blocks the b-barrel transporter LptD
Outer membrane
LPS
PEM
LptD
LptE
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bacteria
5. Bacteriophages and enzybiotics
3. Blockers of virulence factors
4. Nanoparticles and Antibacterial peptides
2. New antibacterial agents 1. Derivative of known antibacterial agents
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enzybiotics
Hermoso J, et al Taking aim on bacterial pathogens: from phage therapy to enzybiotics
Curr Op Microbiol 2007; 10: 461–472
glycosidases
endopeptidases (o endolysins)
Witzenrath M, et al. Systemic use of the endolysin Cpl-1 rescues mice
with fatal pneumococcal pneumonia. Crit Care Med 2009; 37: 642–649
Cpl-1
…
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bacteria
5. Bacteriophages and enzybiotics
3. Blockers of virulence factors
4. Nanoparticles and Antibacterial peptides
2. New antibacterial agents 1. Derivative of known antibacterial agents
6. Other approaches
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Gene-silencing antisense oligomers
• Peptide-conjugated phosphodiamidate morpholino
oligomers (PPMOs) are synthetic DNA/RNA analogues
that silence expression of specific genes
• They are resistant to nucleases
• JID (2013) 208:1553 acpP gene encoding acyl carrier protein from
A. baumannii and A. lwoffii
Peptide PMO
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CONCLUSIONS
• A combination of scientific and economic challenges has posed
significant barriers to the development of novel antibacterials
• Different approaches can be used to develop new strategies to
treat infections caused by pan-drug resistant bacteria
• Public and private sector stakeholders must show greater
commitment to an R+D agenda
• The interplay between the pharmaceutical industry and the
academia/hospital should be improved
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QUESTIONS
• Species-selective compounds versus broad-spectrum
compounds?
• Whole-cell antibacterial assay versus target-based antibiotic
discovery?
• Are coumpounds wich act on targets which are expressed in
vivo during infection and not in vitro lost?
• Are silent operons not expressed in the conditions used to
growth antibiotic-producing microorganims lost?
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QUESTIONS
• Are uncultured bacteria a potential source of new antibiotics?
• Is the old patent literature a good place to start searching?
• Should the new antibiotics be active against persisters and
bacteria in biofilm?