antibiotic antibiotic efflux in procaryotic procaryotic ... · (amk) 22: meropenem (mem) 20:...

1INRA-Toulouse21/05/2010

AntibioticAntibiotic efflux efflux in in procaryoticprocaryotic and and eucaryoticeucaryotic cellscells::

fromfrom molecularmolecular mechanismsmechanisms toto pharmacologicalpharmacological consequencesconsequences

Françoise Van Bambeke, PharmD, PhD

Pharmacologie cellulaire et moléculaireLouvain Drug Research

Institute

Université

catholique de LouvainBruxelles, Belgium

www.facm.ucl.ac.be


Where do I come from ?

"corpora non aguntnisi fixata"

"The goal is

… to findchemical

substances that

have special

affinities

for pathogenic

organisms

and that, like

magic

bullets, go straight to their

targets"

Université

catholique de LouvainLouvain Drug Research

InstituteBrussels


WhyWhy active efflux ?active efflux ?

Manneken Pis, who saved Brussels from fire


Chemotherapeutic agents exert toxic effects on specific target cells

How can these drugsreach their target inside the cells ?

nucleic acids

ribosomes

enzymes


Reaching an intracellular target …

polar drug

lipophilic drug

physico-chemical properties are inadequate for reaching an intracellular target !

Van Bambeke et al. (2000) Biochem. Pharmacol. 60:457-70


Reaching an intracellular target …

amphipathic drug

most drugs are amphipathic by design,to be able to cross membrane barriers !



Intracellular chemotherapeutic agents

But a diffusible compound may have

potentially harmful effects !Van Bambeke et al. (2000) Biochem. Pharmacol. 60:457-70


Why efflux transporters ?

Extrusion by efflux pumps



Why efflux transporters ?

Extrusion by efflux pumps


general mean of protectionagainst cell invasion by diffusible molecules


Typical ‘toxic’ diffusible substances as substrates for efflux pumps

antifungals

anticancer

agents

antibiotics


Most antibiotics do act on intracellular targets

(lipo- and glycopeptides) (-lactams)

Efflux as a mechanism

of resistanceby reducing

antibiotic

concentration inside

the bacteria

quinolones

macrolides aminoglycosides

tetracyclines

sulfamides


Active efflux in Active efflux in bacteriabacteria:: rolerole in in antibioticantibiotic resistanceresistance

Niagara Falls, Canada


FQ efflux pumps in S. pneumoniae

Terry et al., Nature Reviews Microbiology 2005; 3: 566-572

Primary

transporters«

ATP-Binding

Cassette

»

Secondary

transporters(Proton motive force)

PmrAGill et al, AAC 1999; 43:187-9

PatA/PatBMarrer et al, AAC 2006; 50:685-93


Fluoroquinolone antibiotics

ciprofloxacin

N

C

O

FOH

O

OCH3

HN N

moxifloxacin

N

O

OH

O

HNN

F


Selection of resistance by subMIC concentrations of FQ

ciprofloxacin moxifloxacin

Loss of susceptibility; efflux selected by ciprofloxacin Avrain et al, JAC (2007) 60:965-972

no efflux

basal efflux




Loss of susceptibility; efflux selected by ciprofloxacin only Avrain et al, JAC (2007) 60:965-972

no efflux

basal efflux



Expression of genes coding

for efflux pumps

in the absence of fluoroquinolones

Increased efflux due toPatA/PatB

Avrain et al, JAC (2007) 60:965-972


PatA/B are inducible by fluoroquinolones

0 1 2 3 4 5 60

25

50

75

100

125

150

175

MXFCIP

expr

essi

on ra

tio (%

val

ue a

t 4 h

)

0 1 2 3 4 5 60

25

50

75

100

125

150

175CIPMXF

patA patB

time (h) time (h)

Bacteria in the presence of ½ MIC of FQ ATCC49619

El garch et al, ECCMID (2009) O495


Kinetics of induction & reversibility

0 1 2 3 4 5 60

25

50

75

100

125

150

175

MXFCIP

expr

essi

on ra

tio (%

val

ue a

t 4 h

)

0 1 2 3 4 50

25

50

75

100

125

150

175

0 1 2 3 4 5 60

25

50

75

100

125

150

175CIPMXF

0 1 2 3 4 50

25

50

75

100

125

150

175patA patB

time (h) time (h)

4 h with ½ MIC; up to 5 h without FQ ATCC49619

Overexpression

may contribute to resistance during treatment !El garch et al, ECCMID (2009) O495


Efflux in S. pneumoniae: is it important in the clinics ?

MIC of fluoroquinolones in 107 strains collected from patients with AECB

Reserpine reduces MICs !


Efflux in S. pneumoniae: is it important in the clinics ?

Suspected efflux based on phenotypic analysis


Efflux and resistance in P. aeruginosa

Mesaros et al. (2005) Louvain médical. 124:308-20


Efflux and low level of resistance in Pseudomonas aeruginosa

MICs

vs EUCAST breakpoints

for 109 P. aeruginosa without

or with

efflux mechanisms,

isolated

from

ICU patients (VAP)

Riou et al, ECCMID 2010

meropenem

mexA < 2 mexA 20.03125

0.06250.125

0.250.5

1248

163264

128256

mexA expression level

amikacin

mexX < 5 mexX 50.25

0.51248

163264

128256

mexX expression level

MIC

pip-tazo

mexA < 2 mexA 20.03125

0.06250.125

0.250.5

1248

163264

128256

mexA expression level

MexX substr.

MexA substr.

MexA substr.


Efflux selection during treatment

Prevalence of MexA

and MexX

overexpressers

in 62 phylogentically-related pairs of P. aeruginosa isolated from ICU patients (VAP)

DAY x (%)

38.71%

22.58%

20.97%

17.74%

DAY 0 (%)

66.13%

12.90%

11.29%

9.68%

MexA-/MexX-

MexA+/MexX-

MexX+/MexA-

MexA+/MexX+



Efflux selection during treatment


Antibiotic no. patients

Piperacillin-tazobactam

(TZP) 26Amikacin

(AMK) 22Meropenem

(MEM) 20Cefepime

(CEF) 19Ciprofloxacin (CIP) 6

Antipseudomonal antibiotics received by the patients during

treatment

DAY 0 DAY X05

1015

202530

3540

455055

60

0

234

1

nb effluxsystems

num

ber o

f str

ains

global influence of treatment

number of efflux systems detected at day 0 and day X

69% com

binations


Active efflux in Active efflux in eucaryoticeucaryotic cellscells:: rolerole in in antibioticantibiotic PK/PDPK/PD

Old Faithful Geyser


Target accessibility is critical for intracellular activity


Active efflux reduces antibiotic cellular concentration


Consequences of antibiotic efflux from eucaryotic cells

• alteration of pharmacokinetics

• alteration of pharmacodynamics

• single cell: accumulation, localization

• whole

organism: absorption, distribution, elimination

• cellular level: activity

against

intracellular

bacteria

• body level: drug

concentration in the infected

compartment

Van Bambeke et al, JAC (2003) 51:1067-1077


Characterization of antibiotic Characterization of antibiotic efflux pumps in macrophages efflux pumps in macrophages

Belgian beer

37INRA-Toulouse21/05/2010 37

ATP-Binding Cassette transporters

ABCs transporters

ABCA ABCB ABCC ABCD ABCE ABCF ABCG

P-gp MRPs BCRP

multidrug transporters


Fluoroquinolone antibiotics

ciprofloxacin

moxifloxacin

N

O

OH

O

HNN

F

N

C

O

FOH

O

OCH3

HN N


Kinetics of accumulation and efflux for ciprofloxacin

Michot et al. (2004) AAC 48:2673-82

both accumulation and efflux markedly affectedBy probenecid (inhibitors of Mrps)

extracell. conc. 17 mg/L; probenecid 5 mM


Ciprofloxacin, classical model

Kolaczkowski & Goffeau (1997) Pharmacol. Ther. 76:219-42


Kinetics of accumulation and efflux for moxifloxacin

Michot et al. AAC (2005) 49:2429-37

neither accumulation nor efflux affectedBy probenecid

extracell. conc. 17 mg/L; probenecid

5 mM


Quinolones as inhibitors of ciprofloxacin efflux

• ciprofloxacin efflux inhibited by ciprofloxacin

Michot et al. AAC (2005) 49:2429-37



• ciprofloxacin efflux inhibited by ciprofloxacin• moxifloxacin not affected

Michot et al. AAC (2005) 49:2429-37



• ciprofloxacin efflux inhibited by ciprofloxacinmoxifloxacin

CIP MXF

CIP

Michot et al. AAC (2005) 49:2429-37



• ciprofloxacin efflux inhibited by ciprofloxacinmoxifloxacin

CIP MXF

moxifloxacinalso able

to interactwith the transporter !

CIP

Michot et al. AAC (2005) 49:2429-37


Moxifloxacin, ‘futile-cycle’ model

Eytan et al. (1996) JBC 271:12897-902


Influence of efflux pumps Influence of efflux pumps on antibiotic activityon antibiotic activity against intracellular against intracellular

infections infections

Belgian chocolate


Active efflux reduces antibiotic intracellular activity


Models of intracellular infection

L. monocytogenes S. aureus

cytosol phagolysosomes


Influence of pump inhibitors on intracellular activity

azithromycin and L. monocytogenes

verapamil 20 µM; 24 h

L. monocytogenes

AZMAZM

Seral et al. (2003) JAC 51:1167-73


azithromycin and S. aureus

verapamil 20 µM; 24 h

AZMAZM

S. aureus


Seral et al. (2003) JAC 51:1167-73


ciprofloxacin and L. monocytogenes

gemfibrozil 250 µM; 24 h

L. monocytogenes

CIP


Seral et al. (2003) JAC 51:1167-73


ciprofloxacin and S. aureus

gemfibrozil 250 µM; 24 h

CIP

S. aureus


Seral et al. (2003) JAC 51:1167-73


Influence of pump inhibitors on antibiotic distribution

L. monocytogenes

AZMAZM

S. aureus

verapamil enhances azithromycin concentrationIn cytosol and vacuoles

Seral et al. (2003) JAC 51:1167-73


L. monocytogenes

CIP

S. aureus

gemfibrozil enhances ciprofloxacin cytosolic content

Influence of pump inhibitors on antibiotic distribution

Seral et al. (2003) JAC 51:1167-73


Can we make Can we make eucaryoticeucaryotic cells cells «« resistantresistant »» to antibiotics ?to antibiotics ? A way to further characterize A way to further characterize

efflux transporters efflux transporters

J.M. Folon, La Hulpe, Belgium


Over-expression of efflux pumps as mechanism of resistance

How to get resistant cells ?

Gottesman et al, Methods Enzymol. (1998) 292: 248-58

•

step-wise

increase in AB concentration

•

several

passages at

each

step

time and drugconsumming!

multifactorial

multidrug

resistance


Identification of the ciprofloxacin transporter: « resistant » cells as a tool

Chronical exposure to increasing concentrations

Michot et al., Antimicrob. Ag. Chemother. (2006) 50:1689-1695

0.1 mM

0.15 mM

0.2 mM


Ciprofloxacin « resistant » cells: phenotypic analysis

ATP-dependent

reduction

in cell

accumulation of CIP; MXF non affected

control ATP-depleted

CIP MXF0

250

500

750

1000 WT

cellu

lar c

once

ntra

tion

(ng/

mg

prot

)

CIP MXF0

250

500

750

1000 WT




CIP MXF0

250

500

750

1000 WT RS

cellu

lar c

once

ntra

tion

(ng/

mg

prot

)

CIP MXF0

250

500

750

1000 WT RS

ATP-dependent

reduction

in cell

accumulation of CIP; MXF non affected

control ATP-depleted




efflux rate

IC50

gemfibrozil

Marquez et al., Antimicrob. Ag. Chemother. (2009) 53:2410-6


ARNm levels (Real-Time PCR)

expression Mrp2 and Mrp4, but Mrp4 predominates

Ciprofloxacin « resistant » cells: genotypic analysis



Ciprofloxacin « resistant » cells: proteomic analysis

Mrp2

µg 5 15 30 5 15 30

µg 5 15 30 5 15 30

Mrp4

WT RS

WT RS

detection of the proteins by Western-Blot of membrane fraction Confocal

microscopy



Ciprofloxacin « resistant » cells : which transporter ?

Mrp2 Mrp4- CT 10 25 10 25 - CT 5 10 25 2510

Specific extinction of gene expression by siRNA



Acquisition of resistance is a stepwise process

0 50 100 150 2000

20

40

60

80

100

0

5

10

15

ciprofloxacin concentration (µM)to which cells are resistant

cipr

oflo

xaci

n re

sidu

al a

ccum

ulat

ion

(% w

ild-ty

pe c

ells

) Abcc4 m

RN

A ratio

Accumulation and Mrp4 expression during selection of resistance

204060801000

5

10

15

20R2 = 0.994

ciprofloxacin residual accumulation(% wild-type cells)

Abc

c4 m

RN

A ra

tio


Can we select for moxifloxacin « resistant » cells ?


FQ accumulation and gemfibrozil effect

WT

Vallet et al., FEBS-ABC meeting. (2010)




WT

MXF-RS

FQ accumulation and gemfibrozil effect




Ciprofloxacin efflux

T1/2

WT >> T1/2

WT+GEM = T1/2

MXF-RSVallet et al., FEBS-ABC meeting. (2010)


Moxifloxacin-exposed cells are « anti » resistant!

Mrp4 expression

WT MXF-RS CIP RS

Mrp4

WT MXF- -

20µg 40µg 60µg 20µg 40µg 60µg 10µg

Actin

Western-Blot ARNm

(Real Time PCR)



Fluoroquinolone transport: model

ciprofloxacin

inout

41

inout

0.21

inout

151

WT CIP-RS MXF-RS


Fluoroquinolone transport: model

moxifloxacin

inout

151

inout

151

inout

151

WT CIP-RS MXF-RS


Efflux pumps … and what next ?

How to get resistant cells ?

Gottesman et al, Methods Enzymol. (1998) 292: 248-58

•

step-wise

increase in AB concentration

•

several

passages at

each

step

time and drugconsumming!

multifactorial

multidrug

resistance


13C6

-Lys13C6

-Arg12C6

-Lys12C6

-Arg

WT CIP-macrophages

Stable Isotope Labeling Aminoacid in Culture

sample

mixing

1:1

protein

digestion

identification in mass spectrometryand determination

of the relative abundance


13C6

-Lys13C6

-Arg12C6

-Lys12C6

-Arg

WT CIP-macrophages

DiscontinuousSucrose gradient

Enriched plasmamembrane fraction


post-nuclearhomogenate

1.10

1.13

1.15

1.17

1.19

ultracentrifugation

1.10

1.13

1.15

1.17

1.19

F1

F2

F3

F4

F5

MRP1

Prohibitin

190 -

kDa

40 -

F1 F2 F3 F4 F5


13C6

-Lys13C6

-Arg12C6

-Lys12C6

-Arg

WT CIP-macrophages

DiscontinuousSucrose gradient

Enriched plasmamembrane fraction


Combine 1:1

SDS-PAGE/in-gel digestion

Protein ID & Quantification

-

200

-

150

-

120-

100

-

85

-

70-

60

-

40

-

50

-

30

A

B

C

F

DE

G

H

I

J

F2

AB

C

F

DE

F1

G

HIJ

k


SILAC: global data

Identification of 900 proteins with

3 uniques peptides

Among

proteins

detected

in both

fractions

15

expression in CIP-macrophages

as compared

to WT

13


as compared

to WT

Among

proteins

detected

in one of the two

fractions

37/36


as compared

to WT

29/34


as compared

to WT

Marquez et al, FEBS 2009


Proteins with modified expression in CIP-resistant cells


Proteins with modified expression in CIP-resistant cells

Dnajc3

WT CIP-R25 µg 50 µg 25 µg 50 µg

►

WT CIP-R 25 µg 50 µg 25 µg 50 µg

kDa

►Tlr7- 130 -- 100 -

On the same chromosome as mrp4 !

Transports nucleosides/tides

(substrates for Mrp4 !)


Gene amplification in CIP-resistant cellschromosome 14 mrp4 FISH analysis

WT cells

chromosome 14

mrp4

Cells resistant to 0.15 mM

Cells resistant to 0.1 mM


Gene amplification in CIP-resistant cells

chromosome 5

chromosome 13 chromosome 16

Heterogeneity of cell population !

mFISH analysis of CIP-R cells


Gene amplification in CIP-resistant cells

Mrp4 and Dnaj3 co-amplified in CIP-resistant cells

FISH analysis of CIP-R cells

Dnajc3

WT CIP-R25 µg 50 µg 25 µg 50 µg

► Mrp4

Dnajc3


and in moxifloxacin-exposed cells ?

TaqMan Low Density Array of ABC transporters

Cell line gene ciprofloxacin-

resistant moxifloxacin-

resistant Abca1 -1.53a -3.51 Abca2 -1.13 -1.12 Abca3 1.10 -1.56 Abca4 nd nd Abca5 -1.85 2.31 Abca6 nd nd Abca7 -1.36 -1.20 Abca8a nd nd Abca8b (1.39) 76.20 Abca9 (-17.45) (-10.48) Abca13 1.66 2.02 Abca14 nd nd Abca15 nd nd Abcb1a* (-1.38) 76.35 (-1.89) 84.42 Abcb1b 1.03 1.72 Abcb2 1.10 4.30 Abcb3 -1.35 3.17 Abcb4 1.01 2.48 Abcb6 -1.12 -1.22 Abcb8 1.00 -1.25 Abcb9 6.08 9.83 Abcb10 1.40 1.43 Abcb11 (1.15) (1.19)

Cell line gene ciprofloxacin-

resistant moxifloxacin-

resistant Abcc1 1.08 -1.26 Abcc2* (1.44) (-1.26) (9.25) (5.09) Abcc3 -1.15 1.09 Abcc4 14.59 -1.82 Abcc5 -1.26 1.29 Abcc6 nd nd Abcc7 nd nd Abcc8 (1.22) (7.74) Abcc9 nd nd Abcc10 1.01 -1.40 Abcc12 nd nd Abcd1 1.35 2.22 Abcd2 1.10 1.79 Abcd3 -1.04 -1.51 Abcd4 -1.43 -2.03 Abce1 -1.04 -1.00 Abcf2 -1.01 1.21 Abcf3 -1.08 1.11 Abcg1 -1.93 -4.92 Abcg2* (1.12) 108.41 (1.17) 99.47 Abcg3 nd nd Abcg4 (1.62) (-1.07) Abcg5 nd nd Abcg8 nd nd




CT + VER0

50

100

WT cells

MXF-R cells

a

A

b

B*

*

Rhodamine 123

200

300

400

Subs

trat

e ac

cum

ulat

ion

(% o

f con

trol

in w

ild-ty

pe c

ells

CT + FTC

a

a

bB

*

Bodipy prasozin

A

0

50

100

150

P-gp and Bcrp are functional




P-gp and Bcrp are functionalbut do not play a major role in FQ accumulation

CT+ G

EM+ V

ER+ F

TC+ G

EM + VER

+ GEM +

FTC

0

250

500

750

1000

1250

1500 WT cellsMXF-R cells

a

b* **

* *

cd

e

f

AB B

B

C C

ciprofloxacin

cellu

lar c

once

ntra

tion

(ng/

mg

prot

)

CT+ G

EM+ V

ER+ F

TC

a

b

*

bb

A

AA

A

0

250

500

750

1000

1250

1500

moxifloxacin



IncreasedIncreased efflux efflux …….. ConsequencesConsequences for for activityactivity

againstagainst intracellularintracellular bacteriabacteria andand

CooperationCooperation betweenbetween procaryoticprocaryotic and and eucaryoticeucaryotic transporterstransporters

Les aventures de Tintin, Hergé, Belgium


Increased efflux in ciprofloxacin-resistant cells : consequence for antibiotic activity

Lismond et al., Antimicrob. Ag. Chemother. (2008) 52:3040-46

Ciprofloxacin

and Listeria

Wild-type cells

and bacteria


Increased efflux in bacteria

MIC of Listeria strains and effect of reserpine

MIC (mg/L)

quinolone

EGD CLIP

Res. (-) Res. (+) Res. (-) Res. (+)

CIP 1.2 1.0 5.0 1.0

MXF 0.6 0.6 0.5 0.25




Ciprofloxacin

and Listeria

cells

and overproducing efflux pumps

for ciprofloxacin




Ciprofloxacin

and Listeria

bacteria

overproducing efflux pumps

for ciprofloxacin

bacteria

and cells

overproducing efflux pumps

for ciprofloxacin




Moxifloxacin

and Listeria

Wild-type cells

and bacteriacells

and bacteria

overproducing

efflux pumps

for ciprofloxacin



ConclusionsConclusions

Toulouse: fontaines


Food for thought …

• in procaryotic

cells, active efflux truly

contributes

to resistance

need

of appropriate

diagnostic tools selection

of antibiotics

that

are poor

substrates

• in eucaryotic

cells,

active efflux can

modify• pharmacokinetics

(cellular accumulation; barrier

effects)

• pharmacodynamics

(intracellular

activity)

selection

of antibiotics

that

are poor

substrates combinations

with

efflux pumps

inhibitors

?

• expression of efflux pumps

can

be

modified

by exposure

to drugs

reduced

susceptibility

during

treatment cell

metabolism

modifications

same ?


CoworkersCoworkers ……

•

B. Devreese and M. Aerts Proteomics Laboratory for Protein Biochemistry and Biomolecular

Engineering, Ghent University, Belgium

•

E. Jacquet and N. Nhiri TaqMan Low Density Array Institut de Chimie des Substances Naturelles, CNRS, Gif

sur Yvette, France

•

P. Courvalin Resistant strains Unité

des Agents antibactériens,

Institut Pasteur, Paris, France

•

L. Piddock and M. Garvey PatA/PatB Antimicrobial Agents Research Group, University

of Birmingham, UK


Efflux in Efflux in ourour team team ……

www.facm.ucl.ac.be

HOOC

NH2


Let’s dream to the next pump we will discover …

Toulouse: première pompe à gaz naturel pour véhicules

antibiotic antibiotic efflux in procaryotic procaryotic ... · (amk) 22: meropenem (mem) 20:...

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