beta lactam

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KHAÙNG SINH -LACTAMIN (-LACTAM) Azetidin = β-lactamin

Transcript of beta lactam

Page 1: beta lactam

KHAÙNG SINH -LACTAMIN (-LACTAM)

Azetidin = β-lactamin

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CAÙC THUOÁC CHÍNH

Penicillin: (PENAM)

penicillin G; penicillin V

methicillin; oxacillin

ampicillin; amoxicillin;

carbenicillin; ticarcillin

Chất ức chế -lactamase: (OXAPENAM)

sulbactam; acid clavulanic

CARBAPENEM: imipenem

N

S

O

N

O

O

NO

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CAÙC THUOÁC CHÍNH

Cephalosporin (CEPHEM)

Thế hệ I :cephalexin; cephalothin

Thế hệ II: cefoxitin; cefaclor

Thế hệ III: cefotaxime; cefoperazone; ceftriaxone

Thế hệ IV: cefepime

MONOBACTAM: aztreonam

NO

S

NHO

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CÔ CHEÁ KHAÙNG KHUAÅN

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CÔ CHEÁ ÑEÀ KHAÙNG

Vi khuaån ñeà khaùng lactamin theo caùc cô cheá sau:

Ñeà khaùng enzym: VK sản xuất -lactamase

Ñeà khaùng khoâng enzym:

- thay ñoåi tính thaåm thaáu cuûa maøng teá baøo

- bieán maát hoaëc bieán ñoåi caùc PBP (Penicillin Binding

Proteins)

- ‘Efflux pumps’ Vd: multidrug resistance (MDR) pumps

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HOAÏT TÍNH KHAÙNG KHUAÅN

Quan heä caáu truùc – taùc ñoäng

N

O

COOHH

HN

O

O

RH H

12

3

4

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7

Penicillin

N

NH

O

O

R1H H

1

3

4

5

67

S

COOH

R2

N

NH

O

O

RH R1

SO3H

R2

cephalosporin

monobactam

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NHOÙM PENICILLIN

Benzyl penicillin = Penicillin G

Page 11: beta lactam

N

S

COOHH

HN

O

O

R

H H

12

3

4

56

7

Penicillin

N

S

COOHH

H2N

O

H H

12

3

4

56

7

6-aminopenicillinic acid

Danh phaùp IUPAC

Amid- 6 cuûa acid (2S, 5R, 6R-amino-6-dimethyl-3,3-oxo-7-thia-4-aza-

1-bicyclo [3.2.0]-heptan carboxylic).

Danh phaùp thoâng duïng

Penicillin nhö laø nhöõng amid cuûa acid 6-amino penicillanic (6- APA).

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ÑIEÀU CHEÁ

Töø naám Penicillium notatum.

Penicillin G (theâm vaøo moâi tröôøng acid phenylacetic …)

Penicillin V (theâm vaøo moâi tröôøng acid phenoxyacetic …)

60mg/L 20 g/L

Phöông phaùp sinh hoïc

N

S

O

HN

CH3

COO

HH

H

CH3

COCH2

R'

N

SNH

H COO

H H

O

C

OH2CO

R

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ÑIEÀU CHEÁ

Baùn toång hôïp

N

S

COOHH

HN

O

O

R

H H

12

3

4

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Penicillin

N

S

COOHH

H2N

O

H H

12

3

4

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6-aminopenicillinic acid

B-condition = 1. Me2SiCl2 2. n-Bu-OH, -40oC 3. H2O, 0oC

A- condition

B-condition

A-condition = Aclylase

N

S

COOHH

HN

O

O

R1

H H

12

3

4

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Penicillin

N

S

COOHH

H2N

O

H H

12

3

4

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6-aminopenicillinic acid

R'COCl, Et3N

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BAÙN TOÅNG HÔÏP

AMOXICILLIN

N

S

OCOOH

CH3

CH3H2N

6-APA

+ SiCl

CH3

CH3

CH3

trimethylclorosilon

N

S

OCH3

CH3H2N

OO Si

H3C

CH3

CH3

6-aminopenicillanic acidtrimethylsilyl ester

(I)

(I) +

HO

Cl

O

NH2

.HCl

D-(-)2-(4-hydroxyphenyl)-glycylclorid. hydroclorid

N,N-dimethylanilin N

S

OCH3

CH3HN

OO Si

H3C

CH3

CH3

O

NH2

HO

amoxiillin trimethylsilyl ester(II)

(II)H2O, pH 1,3-1,5

N

S

OCOOH

CH3

CH3HN

O

NH2

HO

Amoxcicillin

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Tính chaát vaät lyù

Caùc penicillin döôùi daïng muoái hoaëc daïng acid laø nhöõng boät traéng

khoâng muøi khi tinh khieát.

Phoå UV

Phoå IR: ôû vuøng 1600-1800 cm-1

1760 vaø 1730 cm-1

1700 vaø 1650 cm-1

1600 cm-1

N

S

COOHH

HN

O

O

R

H H

12

3

4

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Penicillin

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Benzylpenicillin K

(BP 2007)

Absorbance (2.2.25)

Dissolve 94.0 mg in water R and dilute to 50.0 ml with the same solvent.

Measure the absorbance of the solution at 325 nm, 280 nm and at the

maximum at 264 nm, diluting the solution, if necessary, for the

measurement at 264 nm. The absorbances at 325 nm and 280 nm do not

exceed 0.10 and that at the maximum at 264 nm is 0.80 to 0.88,

calculated on the basis of the undiluted (1.88 g/l) solution. Verify the

resolution of the apparatus (2.2.25); the ratio of the absorbances is at

least 1.7.

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Tính chaát vaät lyùN

S

COOHH

HN

O

O

R

H H

12

3

4

56

7

PenicillinNăng suất quay cực

Specific optical rotation (2.2.7)

Dissolve 0.500 g in carbon dioxide-free water R and dilute to 25.0

ml with the same solvent. The specific optical rotation is + 270 to +

300, calculated with reference to the dried substance.

Benzylpenicillin K (BP 2007)

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Tính acid

• Taïo muoái natri vaø kali (bền)

Tan trong nöôùc, pha tieâm

Tính chaát hoùa hoïc

N

S

COOHH

HN

O

O

R

H H

12

3

4

56

7

Penicillin

Natri amoxicillin K Benzylpenicillin

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Tính acid

• Taïo muoái vôùi caùc amin:

– Procain penicillin: taùc ñoäng keùo daøi 24-48 h,

– Benethamin penicillin: taùc ñoäng keùo daøi 3-7 ngaøy,

– Benzathin penicillin: taùc ñoäng keùo daøi 2-4 tuaàn.

Tính chaát hoùa hoïc

N

S

COOHH

HN

O

O

R

H H

12

3

4

56

7

Penicillin

Procain benzylpenicillin

Benzathin benzylpenicillin

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Tính acid

• Taïo thaønh nhöõng este, tieàn chaát cuûa PNC coù khaû naêng phoùng thích

trôû laïi caùc khaùng sinh naøy in vivo.

Tính chaát hoùa hoïc

N

S

COOHH

HN

O

O

R

H H

12

3

4

56

7

Penicillin

Bacampicillin HCl

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Tính khoâng beàn cuûa voøng beta lactam

(OH-

hay penicillinase)

- Chuù yù töông kî vôùi

nhöõng chaát coù tính kieàm

penicillinOH

N

S

O

HHNR

O

H

CO2H

HN

S

COOH

C

O

HO

H HR

O

acid penicilloic

S

N COOHROCHN

OHO

- CO2

S

NH

COOHROCHNS

NH

ROCHN CO2H

acid penilloic

ROCHNO

H

penilloaldehyd

HS

COOHH2N+

D-penicillamin

- Phản ứng dị ứng

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Söï alcol phaân vaø amino phaân

N

S

O

NH

CH3

COOH

H

CH3

CR

O

N

S

CO

NH

CH3

COOH

H

CH3

CR

O

DD

Taùc nhaân aùi nhaân saûn phaåm

alcol R'OH R'O ester penicilloic

amin R'-NH-R'' R'-N-R'' amid penicilloic

hydroxylamin NH2OH NH-OH d/c a. hydroxamic

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Sự mở vòng β-lactam được xúc tác bởi các ion kim lọai

(Phức tạo thành với ion kim lọai họat hóa sự tấn công ái nhân)

N

S

CH3

CH3

OO

OM

2+

HNAc

N

OO

OM

2+

HNAc

H H H HS

X

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HN

S

CH3

CH3

COOH

HNCR

O

ONH

OH

N

S

CH3

CH3

COOH

HNCR

O

O

NH2OH

HN

S

CH3

CH3

CO

HNCR

O

ONH

O

Cu2+

Cu O

(xanh ngoc)

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Tính khoâng beàn cuûa voøng beta lactam

(acid mạnh, nóng hoặc HgCl2)

N

S

O

N H H

CH2O2H

R

O

H

H

HN

SN H H

CO2H

R

O

H

O

N

HSN H

CO2H

R

O

O

HN

HSN

CO2H

R

O

O

HN

S

HN

CO2H

R

O

OHO

H H

acid penicilloic

ROCHNO

H

penilloaldehyd

HS

COOHH2N+

D-penicillamin

S

NH

ROCHN CO2H

acid penilloic

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N

S

H

CO NH

COO

C

H

NH2

O

H H

Na

Ampicillin

Na

N

S

H

CO NH

COO

C

H

NH2

O

H HHO

Amoxicillin

N

S

O

HN

CH3

COO

HH

H

CH3

COCH2

R'

N

SNH

H COO

H H

O

C

OH2CO

R

Peni G Peni V

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Kieåm nghieäm

Ñònh tính:

- Phoå IR

- Saéc kyù lôùp moûng

- Phaûn öùng vôùi hydroxylamin, sau ñoù vôùi CuSO4

- Phaûn öùng maøu vôùi acid H2SO

4

- Phaûn öùng maøu vôùi dd formaldehyd trong H2SO

4

N

S

O

HN

CH3

COO

HH

H

CH3

COCH2

R'

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Kieåm nghieäm

Kieåm tinh khieát

- pH

- Naêng suaát quay cöïc

- Caùc taïp chaát thoâng thöôøng: Thí duï kim loaïi naëng

- Caùc taïp chaát lieân quan: Thí duï N,N-dimethylanilin (trong

ampicillin hoaëc amoxicillin) baèng saéc kyù khí.

N

S

H

CO NH

COO

C

H

NH2

O

H H

Na

Ampicillin

Na

N

S

H

CO NH

COO

C

H

NH2

O

H HHO

Amoxicillin

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Kieåm nghieäm

Ñònh löôïng

1. PHÖÔNG PHAÙP OXY HOÙA KHÖÛ

2. PHÖÔNG PHAÙP HPLC

3. PHÖÔNG PHAÙP VI SINH VAÄT

(Xaùc ñònh hoaït löïc cuûa khaùng sinh)

Penicilinphaân huûy

D-penicillamin + acid penaldic

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• Caùc khaùng sinh nhoùm penicillin raát ít ñoäc,

• Tai bieán chuû yeáu do dò öùng,

• Dò öùng nheï gaây ngöùa, noåi meà ñay…

• Dò öùng naëng gaây shock phaûn veä

ÑOÄC TÍNH VAØ TAI BIEÁN

Page 33: beta lactam

PENICILLIN NHOÙM I

Penicillin thieân nhieân

Penicillin G (benzyl penicillin)

Daïng taùc duïng nhanh: Na/K benzyl penicillin

Daïng taùc duïng chaäm: procain PNC, benethamin PNC, benzathin PNC

Penicillin V (phenoxy methyl penicillin)

N

S

O

HN

CH3

COO

HH

H

CH3

COCH2

R'

N

SNH

H COO

H H

O

C

OH2CO

R

Peni G Peni V

Page 34: beta lactam

• Beàn trong moâi tröôøng acid,

haáp thu toát hôn, hoaït chaát

trong huyeát thanh cao hôn,

T1/2

daøi hôn.

• Töø PNC-G: azidocillin,

clometocillin

• Töø PNC-V: pheneticillin,

propicillin, phenbenicillin

PENICILLIN NHOÙM I

Penicillin baùn toång hôïp

X

X

CH

Z

COHN

N

S

O

H H

CH3

CH2

COOH

Z = N3- ; X = H : azidocillin

Z = OCH3- ; X = Cl : clometocillin

O CH

Z

COHN

N

S

O

H H

CH3

CH2

COOH

Z = CH3- : pheneticillin

Z = C2H5- : propicillinZ = C6H5- : phenbennicillin

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Phoå khaùng khuaån heïp, chuû yeáu treân gram (+):

Caàu khuaån gram (+): tuï caàu khoâng tieát

penicillinase, lieân caàu, pheá caàu

Caàu khuaån gram (-): laäu caàu (khuynh höôùng taêng

MIC vaø xuaát hieän nhöõng chuûng ñeà khaùng).

Xoaén khuaån: xoaén khuaån giang mai, leptospira

vaø Borelia burgdorferi.

Tröïc khuaån gram (+): tröïc khuaån gaây beänh baïch

haàu, beänh than, listeria(vieâm maøng naõo),

erysipelothrix (vieâm quaàng).

PENICILLIN NHOÙM I

Phoå khaùng khuaån

KHOÂNG TAÙC DUÏNG TREÂN TRÖÏC KHUAÅN GRAM (-)

Page 36: beta lactam

PENICILLIN NHOÙM II

Meticillin, oxacillin, cloxacillin, dicloxacillin,

• Phoå heïp gaàn gioáng penicillin nhoùm I, nhöng coù khaû naêng

khaùng laïi penicillinase do S. aureus tieát ra.

N

S

O

HN

CH3

COO

HH

H

CH3

CO

O CH3

O CH3

NaMeticillin

Page 37: beta lactam

N

S

O

HN

CH3

COO

HH

H

CH3

COCC

N

O

C CH3

X

Y

Naisoxazolylpenicillin

PENICILLIN NHOÙM II

Meticillin, oxacillin, cloxacillin, dicloxacillin,

X Y-------------------------------------------------------------Oxacillin (Bristopen) H H Cloxacillin (Orbenin) Cl H Dicloxacillin (Dicloxil) Cl Cl Fluocloxacillin (Floxapen) Cl F

Chuù yù: söï ña thay theá laøm giaûm hoaït tính khaùng sinh

Page 38: beta lactam

N

S

O

HN

CH3

COO

HH

H

CH3

COCH2

R'

Theá treân C cuûa chöùc carboxamid (PNC- G):

amin, hydroxyl, carboxylic, sulfonilic

Môû roäng hoaït phoå sang vi khuaån gram aâm

Page 39: beta lactam

PENICILLIN NHOÙM III

S

O

NH

COOH

C

ONH2

HOOC

penicillin N

Dòch nuoâi caáy

Cephalosporium acremonium

(yeáu hôn peni G tren gramdöông,

nhöng coù taùc ñoäng treân gram aâm)

PENICILLIN NHOÙM Ampicillin

1945

Page 40: beta lactam

• Nhoùm III: goàm coù 2 phaân nhoùm IIIA vaø III B:

III-A: khoâng coù nhoùm theá treân amin (NH2):

Ampicillin, Amoxicillin…

III-B: coù nhoùm theá treân amin (NH2):

Azlocillin, Mezlocillin, Piperacillin…

Page 41: beta lactam

PNC NHOÙM III-A Ampicillin, Amoxicillin…

2S,5R,6R)-6-[[(2R)-2-amino-2-phenylacetyl]amino]-3, 3-dimethyl-7-oxo-

4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

(2S,5R,6R)-6-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-

dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,

Page 42: beta lactam

• Phoå cuûa penicillin G coäng theâm moät soá vi khuaån

gram aâm nhö Haemophilus, Escherichia, Proteus

mirabilis, Salmonella, Shigella.

• Moät soá vi khuaån gaây nhieãm truøng maéc phaûi taïi beänh

vieän khoâng nhaïy caûm vôùi nhoùm khaùng sinh naøy:

Enterobacter, Serratia, Proteus indol döông,

Providencia, Bacillus pyocyanic.

Phoå khaùng khuaån III-A

Ampicillin, Amoxicillin…

Page 43: beta lactam

PNC NHOÙM III-B

Azlocillin, Mezlocillin, Piperacillin…

Taùc ñoäng treân caùc maàm ñeà khaùng vôùi ampicillin nhö:

Klebsiella, Enterobacter, Serratia, Pseudomonas…

Piperacilin phoái hôïp vôùi aminosid hoaëc vôùi chaát öùc cheá

betalactamase

Page 44: beta lactam

Na

N

S

H

HN

COOO

H HCOC

H

COO

Ar

Z

S

Z

Na

Na

Ar

Carbenicillin

Carindacillin

Ticarcillin

PENICILLIN NHOÙM IV (α-carboxy-PNC)

Carbenicillin, ticarcillin, carindacillin

Z=phenyl : Carfecillin

N

SHNH H

O

OC

HC

SO3H

COO Na

Sulbenicillin

Beàn veà maët hoùa hoïc

Hoaït tính KK töông tôï caùc

α-carboxy-PNC

Hoaït tính treân tröïc khuaån muû xanh

Ñoàng vaän vôùi aminosid

Ticarcillin hoaït tính 2 laàn maïnh hôn

carbenicillin.

Page 45: beta lactam

PENICILLIN NHOÙM V (6-penicillin)

Temocillin (6 methoxy ticarcillin)

N

S

COOH

O

CH3

CH3

OCH3HNCOCH

COOH

S

Temocillin

Khaùng sinh naøy ít hoaït tính treân caàu khuaån gram(+)

vaø coù hoaït tính trung bình treân vi khuaån Enterobacterie.

Page 46: beta lactam

PENICILLIN NHOÙM VI (Amidino-PNC)

N

S

O

N

CH3

COO

HH

H

CH3

CHNR' Teân hoùa hoïc

Na+

CH2 O CO C(CH3)3(HCl)

Mecillinam

Pivmecillinam(Selexid)

Amidinopenicillin R'

Phoå KK heïp, taäp trung chuû yeáu treân VK gram aâm.

Raát nhaïy caûm: Escherichia coli.

Nhaïy caûm: Yersinia, Salmonella, Shigella, Enterobacter, Citrobacter,

Klebsiella (khoâng saûn xuaát hoaëc saûn xuaát yeáu penicillinase).

Khoâng ñeà khaùng cheùo vôùi ampicillin

N

azepan-1-ylmethanimine

CH NH

Page 47: beta lactam

•CHAÁT ÖÙC CHEÁ β-LACTAMASE

ÑAÏI CÖÔNG

• Nhieàu loaïi vi khuaån coù khaû naêng tieát ra caùc enzym beta

lactamase phaân huûy caùc khaùng sinh hoï beta lactamine.

Söï saûn sinh caùc enzym naøy coù theå laø töï nhieân hay tieáp

nhaän ñöôïc.

• Men beta lactamase bao goàm penicilinase vaø

cephalosporinase.

Page 48: beta lactam

• Chaát öùc cheá beta lactamase + caùc penicillin: môû roäng

phoå khaùng khuaån cuûa nhöõng chaát naøy leân caùc vi

khuaån tieát men penicillinase.

• Sau khi gaén vôùi men penicillinase, caùc chaát naøy seõ bò

phaân huûy.

CÔ CHEÁ TAÙC ÑOÄNG

Page 49: beta lactam
Page 50: beta lactam

Acid clavuclanic (suicide inhibitor)

Thu ñöôïc töø Streptomyces clavuligerus

Caáu truùc clavam (oxapenam)

Ñöôïc söû duïng ôû daïng muoái kali clavuclanat

Caùc phoái hôïp: acid clavuclanic – amoxicillin,

acid clavuclanic – ticarcilin

N

O

C

HH

H

O

CH2OH

HH COOH

Page 51: beta lactam

Caûi thieän treân nhöõng maàm nhaïy caûm saûn xuaát beta

lactamase nhö Neiserria gonorhoeae, Haemophilus,

E. coli, Salmonella….

A. clavuclanic – ticarcillin

Phoái hôïp naøy gia taêng taùc ñoäng treân Staphylococcus

(95% Streptococcus nhaïy caûm vôùi phoái hôïp acid

clavuclanic – ticarcillin so vôùi 49% neáu chæ söû duïng

moät mình ticarcillin).

Phoå khaùng khuaån cuûa phoái hôïp

B. clavuclanic – amoxicillin

Page 52: beta lactam

• Daãn chaát cuûa penam, baùn toång hôïp töø 6 APA

• Caáu truùc töông töï penicillin nhöng khoâng coù nhoùm theá

ôû C6

(maát C*),

• S ôû vò trí 4 ñöôïc oxy hoùa thaønh SO2,

• Caáu hình C2 vaø C5 gioáng penicillin

Sulbactam

(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic

acid 4,4-dioxide

Phoái hôïp sulbactam-ampicillin

N

SHH

H

O H COOH

CH3

CH3

OO

Page 53: beta lactam

- Daãn chaát este đôi từ sulbactam vaø ampicillin

- Hoaït tính treân caàu khuaån gram döông, gram aâm; tröïc

khuaån gram döông, gram aâm

- Ñöôïc duøng trong tai-muûi-hoïng, hoâ haáp, sinh duïc, da…

treân nhöõng maàm nhaïy caûm

Sultamicillin

N

S

CH3

CH3

O

OO

O

N

S

O

H3C

H3C

OO

O

HN

O

NH2

Sultamicillin

Page 54: beta lactam

• Daãn chaát cuûa sulbactam maø moät nhoùm methyl mang

nhoùm theá triazolyl

• Chaát öùc cheá betalactamase khoâng thuaän nghòch phoå

roäng

• Söû duïng döôùi daïng phoái hôïp tazobactam - piperacillin

Tazobactam

N

SHH

H

O H COOH

CH2

CH3

OO

NNN

Page 55: beta lactam

CARBAPENEM

NO

Carbapenem

N

HO

H3C

OCOOH

S

NH2

Thienamycin (1977)

Thienamycin :

- trích töø moâi tröôøng nuoâi caáy Streptomyces cattleya.

- hoaït tính khaùng khuaån roäng

- hoaït tính treân Pseudomonas

- khaùng laïi β-lactamase

SNH2

SNH CH NH

Page 56: beta lactam

IMIPENEM

Acid [hydroxy-1 ethyl (R) ] –6[[(iminomethylamino-2)

ethyl]thio]-3-oxo-7-aza-1bicyclo [3.2.0]hepten-2

carboxylic-2 (5R,6S).

N

HO

H3C

OCOOH

S

NH2

Thienamycin (1977)

N

HO

H3C

OCOOH

S

NH

NH

Imipenem

benzyl formimidat

Page 57: beta lactam

- Nhaân penem vaø nhoùm COOH ôû C2

caàn thieát cho hoaït tính khaùng khuaån.

- C*6 (S) thay vì C*6 (R) ôû penicillin vaø cephalosporin khaùng enzym cuûa VK

- Amino-2-thioethyl (cysteamin) ôû vò trí 3 hoaït tính treân Pseudomonas.

- N-formimidoyl phaân töû beàn veà maët hoùa hoïc.

IMIPENEM

(S)

N

HO

H3C

OCOOH

S

NH

NH

Page 58: beta lactam

IMIPENEM

Phoå khaùng khuaån

Beàn vöõng vôùi men beta lactamase, phoå khaùng khuaån raát roäng, bao goàm:

-Caàu khuaån gram döông: Staphylococcus nhaïy meticillin (Staphylococcus khaùng

meticillin ñeà khaùng vôùi imipenem), Strepococcus (keå caû nhoùm D),

Pneumococcus, Enterococcus.

-Caàu khuaån gram aâm: Neisseria

-Tröïc khuaån gram döông: Clostridium, Listeria monocytogenes…

- Tröïc khuaån gram aâm: H. influenzae, E. coli, Klebsiella, Proteus mirabilis,

Enterobacter, Citrobacter, Serratia, Proteus vulgaris, Bacteroides fragilis,

Acinetobacter, P. aeruginosae.

N

HO

H3C

OCOOH

S

NH

NH

Page 59: beta lactam

IMIPENEM

- IV chaäm.

- Deã bò phaân huûy bôûi dehydropeptidase ôû oáng thaän khi söû duïng thöôøng

keát hôïp imipenem vôùi cilastin (chaát öùc cheá enzym dehydropeptidase) ñeå giôùi

haïn söï chuyeån hoùa naøy.

cilastin

N

HO

H3C

OCOOH

S

NH

NH

Page 60: beta lactam

N

HO

OCO2H

S

HN

NH

Imipenem

Meropenem is more stable to renal dehydropeptidase than imipenem

and use with cilastatin, which inhibits this enzyme, is not required.

N

HO

H3C

O

CH3

CO2H

S

NH

ON

CH3

CH3

Meropenem

Page 61: beta lactam

ME1036. ME1036 (CP5609; developed by Meiji Seika,

licensed by Forest) is a broad-spectrum carbapenem that

binds with a high affinity to PBP 2a of MRSA (IC50 0.13 to

0.73 g/ml) and that exhibits potent in vitro inhibitory

activity against MRSA .

N

HO

OCO2H

S

HN

NH

Imipenem

Page 62: beta lactam

PZ-601 (Razupenem). PZ-601 (formerly known as SMP-

601; licensed from Dainippon Sumitomo Pharma Co., Ltd.,

Osaka, Japan) is a new carbapenem currently being developed

by Protez Pharmaceuticals (now Novartis) that has

demonstrated a high degree of potency against MRSA.

N

HO

OCO2H

S

HN

NH

Imipenem