Strategies to design new antibacterial drugs · antimicrobial agent which circumvents antibacterial...

Jordi Vila Department of Clinical Microbiology Hospital Clinic, Barcelona

Strategies to design new antibacterial drugs

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

bacteria

1. Derivative of known antibacterial agents

• Modification of the basic structure of the

antimicrobial agent which circumvents

antibacterial resistant mechanisms

Derivative of known antimicrobial agents

• Modification of the basic structure of the

antimicrobial agent which circumvents

antibacterial resistant mechanisms


• Development of a compound inhibiting

the mechanisms of resistance for an

antibacterial agent

Blocking antibacterial resistance mechanisms

- Inhibition of beta-lactamases

- Inhibition of efflux pumps

- Inhibition of aminoglycoside-modifying enzymes

- Blocking the SOS response


new inhibitors


A B C D

Clavulanic acid, tazobactam, sulbactam

carbapenemases

AmpC

carbapenemasas





- Inhibition of efflux pumps

- Inhibition of aminoglycoside-modifying enzymes

- Blocking the SOS response


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

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

bacteria

2. New antibacterial agents 1. Derivative of known antibacterial agents

• 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

• 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

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)

bacteria 3. Blockers of virulence factors


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

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

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

bacteria 3. Blockers of virulence factors

4. Nanoparticles and Antibacterial peptides /

peptidomimetics


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

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

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

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

bacteria

5. Bacteriophages and enzybiotics

3. Blockers of virulence factors

4. Nanoparticles and Antibacterial peptides


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

…

bacteria

5. Bacteriophages and enzybiotics

3. Blockers of virulence factors

4. Nanoparticles and Antibacterial peptides


6. Other approaches

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

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

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?

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?

Strategies to design new antibacterial drugs · antimicrobial agent which circumvents antibacterial...

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