THIENAMYCIN

MONOBACTAMS

-LACTAMASE INHIBITORS

1. Thienamycin (Carbapenems)

Acylamino side

chain absent

OH

Plays a role

in -lactamase

resistance

Opposite
stereochemistry
to penicillins

Merck 1976

Carbon

H
H
H3C

NH3
S
N
O
CO2

Double bond leading to

high ring strain and an increase
in -lactam ring reactivity

Carbapenam nucleus

Isolated from Streptomyces cattleya

Potent and wide range of activity vs Gram +ve and Gram -ve
bacteria

Active vs. Pseudomonas aeruginosa

Low toxicity

High resistance to -lactamases

Poor stability in solution (ten times less stable than Pen G)

1. Thienamycin

Thienamycin analogues used in the clinic

H OH
Me

H OH
Me

H OH
Me

NH
HN

Imipenem

N
CO2

H
N

O
C

Me

Meropenem

Me
S

N
CO2

H
N

Me

O
C

Ertapenem(2002)

N
CO2

CO2

In general, the carbapenems have the broadest spectrum of ac=vity of all the -lactam an=bio=cs

2. Monobactams

Nocardicins (Fujisawa 1975)

HO2C

D
HC

H2N

O
CH2

OH

H
N

CH2

H
OH

Nocardicin A

N
C

O
H

CO2H

Monocyclic -lactam ring

Moderately active in vitro vs narrow group of Gram -ve bacteria

Active vs. Pseusomonas aeruginosa

Inactive vs. Gram +ve bacteria

Different spectrum of activity from penicillins

Thought to operate by a different mechanism from penicillins

Low toxicity

2. Monobactams

Clinically useful monobactam

Me
N

Me

CO2H

O
H
N

Me

Aztreonam

H2N
S

N
O

SO3-

Administered by intravenous injection

Can be used for patients with allergies to penicillins and
cephalosporins

No activity vs. Gram +ve or anaerobic bacteria

Active vs. Gram -ve aerobic bacteria

3. -Lactamase inhbitors

-Lactams as substrates/inhibitors of Transpeptidases and -Lactamases

Hydrophobic barrier

Outer
membrane

Porin

Lactamase
enzymes L

L
Periplasmic
space

Cell
membrane

Thin pep=doglycan layer

L

Cell

3. -Lactamase Inhibitors

Clavulanic acid (Beechams 1976)

Sulphur replaced by O
No acylamino

side chain

6
7

OH

3
2
H

CO2H

-Lactam

Oxazolidine ring

Isolated from Streptomyces clavuligerus

Weak, unimportant antibacterial activity

Powerful irreversible inhibitor of -lactamases - suicide substrate

Used as a sentry drug for ampicillin

Augmentin = ampicillin + clavulanic acid

Allows less ampicillin per dose and an increased activity spectrum

Timentin = ticarcillin + clavulanic acid

3. -Lactamase Inhibitors

Clavulanic acid - mechanism of action

1

NH

NH

CH2OH
O

CH2OH

N
O

HN

Base

CO2H
O

OH

CO2H

CH2OH

H2N

NH

NH

O
HN

NH

CO2H

CH

CH2OH

HC
O

CO2H

Irreversibly blocked

3. -Lactamase Inhibitors

Penicillanic acid sulfone derivatives

O
S

Me

2
3

Me
CO2 Na

Sulbactam

Me
N
N

CO2

Tazobactam

Suicide substrates for -lactamase enzymes

Sulbactam has a broader spectrum of activity vs -lactamases than clavulanic acid, but is less
potent

Unasyn = ampicillin + sulbactam

Tazobactam has a broader spectrum of activity vs -lactamases than clavulanic acid, and has
similar potency

Tazocin or Zosyn = piperacillin + tazobactam

Next-genera/on inhibitors

Other drugs which act on bacterial cell wall biosynthesis:

CYCLOSERINE

BACITRACIN

VANCOMYCIN

VANCOMYCIN ANALOGUES

1. Cell Wall Biosynthesis

-Lactams

Growing cell wall

..


..


...

..


...


...


..



...


...


...


...


...


...


...


...



Crosslinking

Cell
membrane

Cytoplasm

Bacitracin

Vancomycin

...




.

Transglycosida/on

Gly

NAG

Carrier
lipid

L-Ala
D-Glu
L-Lys

NAM

L-Ala

Amino acid

D-Ala

Cycloserine

D-Ala- D-Ala

Building block partially constructed in cytoplasm

Transported across cell membrane and completed

Constructed from 2 sugars (NAM, NAG) and a peptide chain

Linked to growing cell wall by enzyme (transglycosidation)

Final crosslinking reaction catalysed by transpeptidase enzymes

2. D-Cycloserine

-Lactams

Growing cell wall

..


..


...

..


...


...


..



...


...


...


...


...


...


...


...



Crosslinking

Cell
membrane

Cytoplasm

Bacitracin

Vancomycin

...




.

Transglycosida/on

Gly

NAG

Carrier
lipid

L-Ala
D-Glu
L-Lys

NAM

L-Ala

Amino acid

D-Ala

Cycloserine

D-Ala- D-Ala

Natural product produced by Streptomyces garyphalus

Inhibits L-alanine racemase and D-Ala-D-Ala ligase

Blocks biosynthesis of D-Ala-D-Ala

Mimics the structure of D-Ala

2. D-Cycloserine

H
N

HO
O
H

NH2
D-Cycloserine

Me

O
H
NH2

D-Alanine

Natural product produced by Streptomyces garyphalus

Inhibits L-alanine racemase and D-Ala-D-Ala ligase

Blocks biosynthesis of D-Ala-D-Ala

Mimics the structure of D-Ala

3. Bacitracin

-Lactams

Growing cell wall

..


..


...

..


...


...


..



...


...


...


...


...


...


...


...



Crosslinking

Cell
membrane

Cytoplasm

Bacitracin

Vancomycin

...




.

Transglycosida/on

Gly

NAG

Carrier
lipid

L-Ala
D-Glu
L-Lys

NAM

L-Ala

Amino acid

D-Ala

Cycloserine

D-Ala- D-Ala

Polypeptide produced by Bacillus subtilis

Binds to the carrier lipid

Prevents the carrier lipid from transporting the NAM pentapeptide building block across the cell membrane

4. Vancomycin and vancomycin analogues

-Lactams

Growing cell wall

..


..


...

..


...


...


..



...


...


...


...


...


...


...


...



Crosslinking

Cell
membrane

Cytoplasm

Bacitracin

Vancomycin

...




.

Transglycosida/on

Gly

NAG

Carrier
lipid

L-Ala
D-Glu
L-Lys

NAM

L-Ala

Amino acid

D-Ala

Cycloserine

D-Ala- D-Ala

Narrow spectrum bactericidal glycopeptide

Produced by Streptomyces orientalis

Blocks transglycosidation

4. Vancomycin and vancomycin analogues

HO

CH2OH

Me

H3N

HO

HO

Me

O
HO

O
OH H3C

Cl
O

H
N
H
N

Vancomycin

Cl

H H
N

CO2

CH3

O
H

O
N

O
H
N
H

N
H

H
NH2Me

Peptide chain

CONH2
HO

OH
OH

Important antibacterial agent

Caps the building block used in the synthesis of the bacterial cell wall

Contains a peptide chain which forms hydrogen bonds to the target

Vancomycin acts as a receptor for the building block

4. Vancomycin and vancomycin analogues

Biosynthesis of vancomycin

Glycosidations
C hlorinatio n

C hlorinatio n

H ydroxylation

OH

O
HO2C

H
N

H
N

N
H
O

HO

H ydroxylation

Tyr

Tyr

O
H
N

N
H
O

H2NOC

NHMe

N
H
O

Asn

Val

OH
OH

Oxidative couplings

Derived from a flexible hexapeptide

Cyclisations result in a rigid structure

Peptide backbone is held in a fixed conformation

4. Vancomycin and vancomycin analogues

Mechanism of
inhibition

Vancomycin

Building
block

Cell membrane

Notes

Vancomycin provides binding pocket for tail of biosynthetic building block

Vancomycin binds to the tail of the building blocks peptide chain

Caps the building block

Disguises the building block from the transglycosidation enzyme

4. Vancomycin and vancomycin analogues

Growing cell wall

..


..



.

.

.


..


.

Vancomycin
dimer

Building
block

Dimerisation occurs

Dimer is highly stable

Large vancomycin molecule
acts as a steric shield

4. Vancomycin and vancomycin analogues

HO

CH2OH

Me

H3N

HO

HO

Me

Cl

O
C

HO

O
D

OH H3C

Cl
O

H
N
H
N

H H
N

O
H

O
N

O
H

CO2

N
H

CH3

N
H

H
NH2Me

CONH2

A
HO

OH
OH

O
Cell wall building block

H
N
H

Me

N
O Me

H-bonding interactions
between the peptide backbone
of vancomycin and the
biosynthetic building block

O

L-Lys-D-Ala-D-Ala

'tail'

4. Vancomycin and vancomycin analogues

Binding interactions

O
in dimer

Heptapeptide
backb one

R1

H
N

N
O

Me

Cell wall building block

R7

H
O

N
R4

R2
R6
H
O

CO2

O
R6
R2

R4
O

N
R5

N
H

H
N
H

Me

R1
NH2Me

N
O Me

H
H

R3

O
N

R7

Cell
Cellwall
wallbuilding
buildingblock
block

N
N

O2C

R5
N

D-Ala-D-Ala-L-Lys- tail

R3

NH2Me
H
N

Me

O
H

L-Lys-D-Ala-D-Ala tail

Heptapeptide
backb one

4. Vancomycin and vancomycin analogues

Drug resistance

Vancomycin-resistant Staphylococcus aureus (VRSA) (1996)

Vancomycin-resistant enterococci (VRE) (1989)

Resistance due to mutation in pentapeptide chain of cell wall building block

Terminal D-alanine replaced by D-lactate

O
Cell wall building block

H
N
H

Me

O
H
N

O Me

L-Lys-D-Ala-D-Ala

Mutation
O

Cell wall building block

N
H

O Me

H
tail

L-Lys-D-Ala-D-Lactate

Me

tail

Peptide link replaced by ester link

Loss of NH (HBD)

Weakens binding affinity of vancomycin with tail

Lactate acts as a leaving group in cell wall synthesis

O
H

4. Vancomycin and vancomycin analogues

Teicoplanin

HO

CH2OH

Alkyl anchor

HO
N
H

OH
HO

O
O

NHAc

C
HO

O
O

Cl

E
OH

Cl
O

H
N
H

Heptapeptide backbone
N

H H
N

O
N
H

CO2

O
NH3

O
H
N

H
B
OH

HO
A
HO

O
HO

OH

O
OH

HO
OH

4. Vancomycin and vancomycin analogues

Teicoplanin

Isolated from a soil micro-organism
Does not dimerise
Alkyl chain anchors the an/bio/c to the outer surface of the cell membrane
Less toxic than vancomycin

Teicoplanin
Building
block

Alkyl chain anchor

Cell membrane

4. Vancomycin and vancomycin analogues

Eremomycin - naturally occurring glycopeptide

H3N

Me

HO

HO

Me
H3N

CH2OH

HO

O
O

Me

O
Me

Cl

HO

H
N
H
N

OH H3C

O
O

H H
N

CO2

O
H

O
N

O
H
N
H

H
CONH2
HO

OH
OH

N
H

H
NH2Me

CH3

4. Vancomycin and vancomycin analogues

LY 333 328 - analogue of eremomycin

Biphenyl hydrophobic tail

Me

CH2 NH2 Me
HO

Me
H3N

HO

CH2OH

HO

O
O

Me

O
Me

Cl

HO

H
N
H
N

OH H3C

Cl

O
O

H H
N

O
H

O
N

CO2

CH3

O
H
N
H

N
H

H
NH2Me

CONH2
HO

OH
OH

1000 x more active than vancomycin

4. Vancomycin and vancomycin analogues

Telavancin - analogue of eremomycin

HN
NH2 Me
HO

HO

Me

CH2OH

HO

O
O

Cl

HO

Hydrophobic tail

OH H3C

Cl
O

H
N
H
N

H H
N

O
H

O
N

CO2

CH3

O
H
N
H

N
H

H
NH2Me

CONH2
OH
OH

HO
N
H

O
P

OH

OH

Approved in 2009 for skin infections

4. Vancomycin and vancomycin analogues

Simplification

Simplified structures capable of binding D-Ala-D-Ala or D-Ala-D-Lac

Lead compounds for further development

OH
O
H3C
O
AA1-AA2-AA3

H
N

O
N

O
H
N
H

CONH2

N
H

H
NH2Me

CH3

Summary of antibacterial targets of cell wall biosynthesis

-Lactams

Growing cell wall

..


..


...

..


...


...


..



...


...


...


...


...


...


...


...



Crosslinking

Cell
membrane

Cytoplasm

Bacitracin

Vancomycin

...




.

Transglycosida/on

Gly

Carrier
lipid

L-Ala
D-Glu
L-Lys

NAM

L-Ala

Amino acid

D-Ala

Cycloserine

D-Ala- D-Ala

NAG

An=bio=cs ac=ng on other target

On the plasma membrane structure
Impair protein synthesis : transla=on
On nucleic acid transcrip=on and replica=on

An=bio=cs ac=ng on the plasma membrane structure

Valinomycin and
gramicidin A
Polymyxin B
Daptomycin

An=bio=cs ac=ng on the plasma membrane

structure: polymyxin

Isolated from a soil bacterium

Bacillus polymyxa
Binds to plasma membrane
Causes the leakage of small
molecules such as
nucleosides from the cell

An=bio=cs ac=ng on the plasma membrane

structure: daptomycin

Isolated from Streptomyces

roseoporus.
FDA 2003, by Cubist.
Ac=ve against Gram-posi=ve
bacteria, including
glycopep=de-resistant
enterococci, methicillin-
resistant staphylococcus
aureus (MRSA), et al.
Skin and soW =ssues
infec=ons.

Total synthesis and medicinal chemistry of

daptomycin

An=bio=cs impairing protein synthesis : transla=on

Aminoglycoside
Tetracycline
Chloramphenicol
Macrolide
Lincosamide
Streptogramins
Oxazolidinones

Aminoglycosides: streptomycin

Oxazolidinones

Synthe=c an=bio=cs
Linezoid (rst of this class of compounds), in 2000; $ 716 m ne^ng sales by 2010;
bacteriosta=c against gram-posi=ve bacteria including MRSA, VER and
Streptococcus pneumoniae; Serious adverse eects: bone marrow suppression,
peripheral and op=c neuropathy, lac=c acidosis and serotonin syndrome.
Radezolid, 10,000 =mes more potent (in clinical trials)

The oxazolidinones bind to the 50S ribosomal subunit and interfere with forma=on of the
complex that associates the mRNA, the f-met-tRNA, and the 50S ribosomal subunits

An=bio=cs on nucleic acid transcrip=on and

replica=on
Quinolones and
uoroquinolones
Aminoacridines
Rifamycins
Nitroimidazoles and
nitrofurantoin

An=bio=cs on nucleic acid transcrip=on and

replica=on
Quinolones and
uoroquinolones

An=bio=cs on nucleic acid transcrip=on and

replica=on
Quinolones and
uoroquinolones

Bacterial resistance to an=bio=cs

and Needs for new an=bio=cs

Bacterial resistance to an=bio=cs

Bacterial resistance
An=microbial compounds almost always require access into
the bacterial cell to reach their target site where they can
interfere with the normal func=on of the bacterial
organism. Porin channels are the passageways by which
these an=bio=cs would normally cross the bacterial outer
membrane. Some bacteria protect themselves by
prohibi=ng these an=microbial compounds from entering
past their cell walls. For example, a variety of Gram-
nega=ve bacteria reduce the uptake of certain an=bio=cs,
such as aminoglycosides and beta lactams, by modifying
the cell membrane porin channel frequency, size, and
selec=vity. Prohibi=ng entry in this manner will prevent
these an=microbials from reaching their intended targets
that, for aminoglycosides and beta lactams, are the
ribosomes and the penicillin-binding proteins (PBPs),
respec=vely.

This strategy have been observed in:
Pseudomonas aeruginosa against imipenem (a beta-lactam
an=bio=c)
Enterobacter aerogenes and Klebsiella spp. against
imipenem
Vancomycin intermediate-resistant S. aureus or VISA strains
with thickened cell wall trapping vancomycin
Many Gram-nega=ve bacteria against aminoglycosides
Many Gram-nega=ve bacteria against quinolones

Bacterial resistance
To be eec=ve, an=microbial agents must also be present
at a suciently high concentra=on within the bacterial
cell. Some bacteria possess membrane proteins that act
as an export or eux pump for certain an=microbials,
extruding the an=bio=c out of the cell as fast as it can
enter. This results in low intracellular concentra=ons that
are insucient to elicit an eect. Some eux pumps
selec=vely extrude specic an=bio=cs such as macrolides,
lincosamides, streptogramins and tetracyclines, whereas
others (referred to as mul=ple drug resistance pumps)
expel a variety of structurally diverse an=-infec=ves with
dierent modes of ac=on.

This strategy has been observed in:
E.coli and other Enterobacteriaceae against tetracyclines
Enterobacteriaceae against chloramphenicol
Staphylococci against macrolides and streptogramins
Staphylococcus aureus and Streptococcus pneumoniae
against uoroquinolones

Eux pumps
These eux pumps are variants of membrane pumps possessed by all bacteria, both pathogenic and non-pathogenic, to
move lipophilic or amphipathic molecules in and out of the cells. Some are used by an=bio=c producers to pump
an=bio=cs out of the cells as fast as they are made, and so cons=tute an immunity protec=ve mechanism for the bacteria
to prevent being killed by their own chemical weapons (Walsh, 2000)

Bacterial resistance

rst evidence of an/microbial resistance

The rst an=bio=c resistance mechanism described was that of
penicillinase. Its presence and ac=vity was rst reported by Abraham
and Chain in 1940 shortly aWer its discovery (Abraham, E. P. and E.
Chain. 1940. An enzyme from bacteria able to destroy penicillin.
Nature 146: 837)

Another means by which bacteria preserve

themselves is by destroying the ac=ve
component of the an=microbial agent. A
classic example is the hydroly=c deac=va=on
of the beta-lactam ring in penicillins and
cephalosporins by the bacterial enzyme
called beta lactamase. The inac=vated
penicilloic acid will then be ineec=ve in
binding to PBPs (penicllin binding proteins),
thereby protec=ng the process of cell wall
synthesis.

This strategy has also been observed in:
Enterobacteriaceae against chloramphenicol
(acetyla=on)
Gram nega=ve and Gram posi=ve bacteria
against aminoglycosides (phosphoryla=on,
adenyla=on, and acetyla=on)

Bacterial resistance to penicillins

Bacterial resistance
Some resistant bacteria evade an=microbials by
reprogramming or camouaging cri=cal target sites to
avoid recogni=on. Therefore, in spite of the presence
of an intact and ac=ve an=microbial compound, no
subsequent binding or inhibi=on will take place.

This strategy has been observed in:
Staphylococci against methicillin and other beta-
lactams (Changes or acquisi=on of dierent PBPs that
do not suciently bind beta-lactams to inhibit cell wall
synthesis.)
Enterococci against vancomycin (altera=on in cell wall
precursor components to decrease binding of
vancomycin)
Mycobacterium spp. against streptomycin
(modica=on of ribosomal proteins or of 16s rRNA)
Muta=ons in RNA polymerase resul=ng in resistance to
the rifamycins;
Muta=ons in DNA gyrase resul=ng in resistance to
quinolones

Examples of bacterial resistance due to target

site modica=on
Altera/on in penicillin-binding protein (PBPs) leading to reduced anity
of beta-lactam an/bio/cs (Methicillin-Resistant Staphylococcus aureus, S.
pneumoniae, Neisseria gonorrheae, Group A streptococci, Listeria
monocytogenes)
Changes in pep/doglycan layer and cell wall thickness resul/ng to
reduced ac/vity of vancomycin: Vancomycin-resistant S. aureus
Changes in vancomycin precursors reducing ac/vity of vancomycin:
Enterococcus faecium and E. faecalis
Altera/ons in subunits of DNA gyrase reducing ac/vity of
uoroquinolones:
Altera/on in subunits of topoisomerase IV leading to reduced ac/vity of
uoroquinolones: Many Gram posi=ve bacteria, par=cularly S.auerus and
Streptococcus pneumoniae
Changes in RNA polymerase leading to reduced ac/vity of rifampicin:
Mycobacterium tuberculosis

Bacterial resistance to vancomycin

Co-occurring of mul=ple mechanisms of resistance

Summary of mechanisms of bacterial resistance to an=bio=cs

An/bio/c (Class)

Target

Resistance mechanism

Inhibitors of murein synthesis

Fosfomycin (expoxide)

Enzyme MurA

Destruc=on by ring-opening
expoxidase; muta=onal inac=va=on
of the glycerophosphate transporter

Cycloserine

Alanine racemase and D-

alanine ligase

Muta=ons in target enzymes

Moenomycin

Transglycosylase

Not fully understood

Bacitracin

Undecaprenol
pyrophosphate (UPP)

Overexpression of compe=ng UPP

phosphatase

Vancomycin

D-Ala-D-Ala on lipid II
pentapep=de

Replacement of D-Ala-D-Ala with D-

Ala-D-Lac

Penicillins/
Cephalosporins/
Carbapenems/
Monobactams

-lactam anibio=cs targt

transpep=dases that
cross-link pep=doglycan
chains in the bacterial cell
wall

Most commonly through

deac=va=on by -lactamase; MRSA
express enzyme with low an=bio=c
binding anity; muta=on of porins

Summary of mechanisms of bacterial resistance to an=bio=cs

An/bio/c (Class)

Target

Resistance mechanism

Inhibitors of mycoic acid synthesis

Isoniazid

Ac=vated by KatG; adduct Expression of impaired KatG;

inhibits InhA
muta=ons on InhA

Inhibitor of ribosomal protein synthesis

Fusidic acid (steroid)

Pep=de elonga=on factor Muta=ons in EF-G

G (EF-G)

Streptomycin
(aminoglycoside)

Ribosomal A-site (protein Muta=ons on S12 and 16S RNA;

S12, 16S rRNA)
modica=on by aminoglycoside
acetyltransferase,
phosphotransferases and
nucleo=dyltransferasel eux

Chlortetracycline
(tetracycline)

16S rRNA

Eux; expression of tetracycline

binding proteins; oxida=on by TetX

Puromycin

An=metabolite of
aminoacyl-tRNA

Modied by puromycin
acetyltransferase

Summary of mechanisms of bacterial resistance to an=bio=cs

An/bio/c (Class)

Target

Resistance mechanism

Mupirocin

Isoleucyl-tRNA synthetase Expression of resistant enzyme

Oxazolidinones

23S rRNA

Muta=ons of 23S rRNA

Chloramphenicol

23S rRNA

Modied by chloramphenicol
acetyltransferases; muta=on of
porins

Pleuromu=lin

23S rRNA

Muta=on of 23S rRNA

Erythromycin
(macrolide)

23S rRNA

Methyla=on and muta=on of 23S

rRNA; modica=on by macrolide
esterases or phosphotransferases;
eux

Lincomycin
(lincosamide)

23S rRNA

Methyla=on and muta=on of 23S

rRNA; lincosamide
nucleo=dyltransferases

Streptogramin

23S rRNA

Methyla=on and muta=on of 23S

rRNA; streptogramin
acetyltransferases

Summary of mechanisms of bacterial resistance to an=bio=cs

An/bio/c (Class)

Target

Resistance mechanism

Inhibitors of DNA and RNA synthesis

Novobiocin

DNA gyrase

Muta=ons of DNA gyrase; eux

Nalidixic acid

DNA gyrase

Eux; muta=on of porins; muta=on

of DNA gyrase

Rifampicin

RNA polymerase

Muta=on of RNA polymerase; ADP-

ribosyla=on of drug; eux

Metronidazole

DNA strands

Reduced drug ac=va=on; eux

Inhibitors of folate metabolism

Sulfonamide

Dihydropteroate synthase Muta=on of DHPS

(DHPS)

Trimethoprin

Dihydrofolate reductase
(DHFR)

Muta=on or overexpression of DHFR

Polymyxin B

Lipid A core of
lipopolysaccharide (LPS)

Modica=ons on LPS

Daptomycin

Phospha=dylglycerol in
cytoplasmic membrane

Changes in membrane lipid

composi=on

Cell membrane disrup/on

Needs for new an=bio=cs: the ESKAPE bugs

Enterococcus faecium (VRE)
Staphylococcus aureus (MRSA)
Klebisella pneumoniae
Acinetobacter baumanni
Pseudomonas aeruginosa
Enterobacter species
They currently cause the majority of US hospital
infec=ons and eec=ve escape the eects of
an=bacterial drugs. JID 2008, 197, 1079

Challenges in developing an=bio=cs

An=bio=c drug discovery and development ow chart adapted from literature versions

Challenges in developing an=bio=cs

Prospects for new an=bio=cs

Synthe=c tailoring of an=bio=c core structures leading to successive genera=ons of an=bio=c classes has
been the mainstay of an=bio=c drug development for the past 50 years. Core scaolds are shown in
black and peripheral chemical deriva=za=ons are shown in white. The quinolone/uoroquinolone
scaolds are of synthe=c origin, while all other scaolds are natural products or their semisynthe=c
deriva=ves.

Prospects for new an=bio=cs

New an=bio=c core scaolds are desperately
needed!
New molecular targets?
New screening strategies?