KHANG SINH -LACTAMIN (-LACTAM)

Azetidin = -lactamin

CAC THUOC CHNH

Penicillin: (PENAM) penicillin G; penicillin V methicillin; oxacillin ampicillin; amoxicillin; carbenicillin; ticarcillin

S N O

Cht c ch -lactamase: (OXAPENAM) acid clavulanic

O N

O
CARBAPENEM: imipenem

N O

CAC THUOC CHNH

Cephalosporin (CEPHEM)

S N

Th h I : Th h II: Th h III: Th h IV: Th h V:

O cephalexin; cephalothin cefoxitin; cefaclor cefotaxime; cefoperazone; ceftriaxone cefepime ceftobiprole

aztreonam

MONOBACTAM:

NH O

C CHE KHANG KHUAN

C CHE KHANG KHUAN

Transpeptidases = Penicillin-binding proteins (PBP) = Protine de liaison aux pnicillines (PLP)

Drugs that inhibit the cross-linking of the peptidoglycan chains The final step in the formation of the cell wall is the completion of the cross-links. This converts the water-soluble and therefore mobile peptidoglycans into the insoluble stationary cell wall. Investigations using Staphylcoccus aureus indicated that the cross-linking is brought about by a multistep displacement of the terminal alanine of the peptide attached to one peptidoglycan chain and its replacement by the terminal glycine of the peptide attached to a second peptidoglycan chain (Fig. 7.26). This reaction is catalysed by transpeptidases.

C CHE E KHANG
Vi khuan e khang lactamin theo cac c che sau: e khang enzym: VK sn xut -lactamase e khang khong enzym: - thay oi tnh tham thau cua mang te bao - bien mat hoac bien oi cac PBP - Efflux pumps Vd: multidrug resistance (MDR) pumps

Th d: S khng ca Staphylococcus aureus

- Sx penicillinases
- Thay i PBP: PBP 2a tm thy trong MRSA (Methicillinresistant Staphylococcus aureus)

(A) Stereo view of the active site of PBP 2a of S. aureus depicted as a solvent-accessible surface (green). The side chains of the active-site serine and lysine are shown as capped sticks and colored by atom types (carbon in gray, oxygen in red, and nitrogen in blue). The backbone of the loop that caps the active site is shown as an orange wire. (B) Stereo view of the active site from the same perspective shown in panel A, except the loop is now shown as a solvent-accessible surface for both the backbone and the side chain functionalities. The presence of the loop blocks the active-site access for molecules the size of typical lactam antibiotics.

The development of new lactam antibiotics that inhibit PBP 2a is significant progress and offers a glimmer of hope for the future treatment of MRSA infections, including those caused by vancomycin-resistant and -intermediate strains.

HOAT TNH KHANG KHUAN

Quan he cau truc tac ong
R HN O 6 7 O N H

R1
H O 5 3 COOH H 2 4

NH O 7 O

H 6 N

H S

5 4 3 R2

1
COOH

Penicillin

R NH O N O
monobactam

cephalosporin

R1 R2 SO3H

NHOM PENICILLIN

Benzyl penicillin = Penicillin G

R HN O H H S

H2N

H S

6 7
O N

6
3

5
O

5
N

3
COOH H 2

COOH H 2

Penicillin
Danh phap IUPAC

6-aminopenicillinic acid

Amid- 6 cua acid (2S, 5R, 6R-amino-6-dimethyl-3,3-oxo-7-thia-4-aza1-bicyclo [3.2.0]-heptan carboxylic). Danh phap thong dung Penicillin nh la nhng amid cua acid 6-amino penicillanic (6- APA).

IEU CHE
H H CH2 CO HN N O H S CH3 CH3 COO R'

H2 O O C C NH H H N O H

S COO

Phng phap sinh hoc T nam Penicillium notatum.

Penicillin G (them vao moi trng acid phenylacetic ) Penicillin V (them vao moi trng acid phenoxyacetic )

60mg/L

20 g/L

IEU CHE

Ban tong hp
R HN O H H S

4
A- condition

H2 N

H S

6 7
O N

5 3
COOH H 2

6 7
O N

5 3
COOH H 2

B-condition

Penicillin
A-condition = Aclylase B-condition = 1. Me2SiCl2
2. n-Bu-OH, -40oC 3. H2O, 0oC
R1 H2N H H S

6-aminopenicillinic acid

4
R'COCl, Et3N
O

HN

H S

6 7
O N

5 3
1

6 7
O N

5 3
COOH H 2

COOH H 2

6-aminopenicillinic acid

Penicillin

BAN TONG HP AMOXICILLIN

O N H 2N COOH CH3 S CH3 6-APA + CH 3 Cl Si CH 3 CH 3 trimethyl clorosilon O N H 2N O H 3C CH3 O Si CH3 CH3

S CH3

6-aminopenicillanic acid trimethylsilyl ester (I) O H3C CH3 O Si CH3 CH3

HO (I) +

O Cl NH2

.HCl N,N-dimethylanilin HO O

O N HN NH 2

S CH3

D-(-)2-(4-hydroxyphenyl)-glycyl clorid. hydroclorid

amoxiillin trimethylsilyl ester (II)

O (II) H2 O, pH 1,3-1,5 HO O HN NH 2 N

COOH CH3 S CH3

Amoxcicillin

R HN O H H S

Tnh chat vat ly

O

6 7
N

5 3
COOH H 2

Cac penicillin di dang muoi hoac dang acid la nhng bot trang khong mui khi tinh khiet. Pho UV
Benzylpenicillin K (BP 2007) Absorbance (2.2.25)

Penicillin

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.

Tnh chat vat ly

Pho IR: vung 1600-1800 cm-1 1760 va 1730 cm-1 1700 va 1650 cm-1 1600 cm-1

Tnh chat vat ly Nng sut quay cc

Benzylpenicillin K (BP 2007)

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.

Tnh chat hoa hoc

R HN O H H S

6 7
O N

5 3
COOH H 2

Tnh acid
Tao muoi natri va kali (bn) Tan trong nc, pha tiem

Penicillin

Natri amoxicillin K Benzylpenicillin

Tnh chat hoa hoc

Tnh acid Tao muoi vi cac amin: Procain penicillin: tac ong keo dai 24-48 h,

R HN O H H S

6 7
O N

5 3
COOH H 2

Penicillin

Benethamin penicillin: tac ong keo dai 3-7 ngay,

Benzathin penicillin: tac ong keo dai 2-4 tuan.

Procain benzylpenicillin

Benzathin benzylpenicillin

Tnh chat hoa hoc

Tnh acid

R HN O H H S

6 7
O N

5 3
COOH H 2

Penicillin

Tao thanh nhng este, tien chat cua PNC co kha nang phong thch tr lai cac khang sinh nay in vivo.
O R= H2 N H H N O O N S O O CH3 CH3 COOR Me R= O O O Me Bacampicillin R= O Talampicillin CMe3 Pivampicillin

Tin dc ampicillin gip hp thu KS tt hn qua rut

Esterase

Penicillin
O H

O O

OMe 3

Penicillin
O H

Penicillin
O

OH

CH 2O

C ch thy phn acyloxymethyl ester bi esterase

Tnh khong ben cua vong beta lactam

.. C NR 2 : O: R R C : O: .. N

R R

Comparison of tertiary amide and -lactam carbonyl groups

Tnh khong ben cua vong beta lactam (OH- hay penicillinase)
R penicillin OH O H H H N S O N CO2 H O H H S R HO C HN O COOH acid penicilloic

S S ROCHN N H acid penilloic CO2H ROCHN N H COOH - CO2 ROCHN O

S N OH COOH

H ROCHN O +

HS H2 N

- Chu y tng k vi nhng chat co tnh kiem

COOH

-Phn ng d ng

penilloaldehyd

D-penicillamin

- nh lng

S alcol phan va amino phan

C O

NH

H S N CH3 CH3 COOH R C O NH

H S CO N D CH3 CH3 COOH

O D

Tac nhan ai nhan alcol R'OH amin R'-NH-R'' hydroxylamin NH2OH R'O R'-N-R'' NH-OH

san pham ester penicilloic amid penicilloic d/c a. hydroxamic

H R C N O O N

CH 3 CH 3

H R C N NH 2OH O O HN NH OH

CH 3 CH 3

COOH Cu2+

COOH

H R C N O O

CH 3

HN CH 3 NH CO O Cu O

(xanh ngoc)

S m vng -lactam c xc tc bi cc ion kim lai (Phc to thnh vi ion kim lai hat ha s tn cng i nhn)

2+

O N S

O Ac HN

O CH 3 CH 3 Ac

2+

O N

O HN

O X S

H H

H H

Ch : vng -lactam b m, KS mt tc dng

Tnh khong ben cua vong beta lactam (acid mnh, nng hoc HgCl2)
R O O H H NH H N CH2 O2 H R S O O H NH H HN CO2H S

Peni G bn pH= 6-7. Hat tnh KS gim rt nhanh pH <5,5 hoc pH 8

R R O HO H H H N HN O CO2H O O O S R N

NH

HS N

CO2H

HS HN CO2H

acid penicilloic

S ROCHN N H acid penilloic CO2 H

H ROCHN O +

HS H 2N

COOH

penilloaldehyd

D-penicillamin

X = NH2, Cl, PhOCONH, heterocyles

H H CH2 CO HN N O H S CH3 CH3 COO R'

H2 O O C C NH H H N O H

S COO

Peni G

Peni V

H H C NH2 O H CO NH N COO Na H S

H H HO C NH2 O CO NH N H COO Na H S

Amoxicillin

Ampicillin

Kiem nghiem

nh tnh: - Pho IR - Sac ky lp mong

H CH2 CO HN

H S N CH3 CH3 H COO R'

- Phan ng vi hydroxylamin, sau o vi CuSO4 - Phan ng mau vi acid H2SO4

- Phan ng mau vi dd formaldehyd trong H2SO4

Kiem nghiem
Kiem tinh khiet - hp thu UV - pH

- Nang suat quay cc

- Cac tap chat thong thng: Th du kim loai nang - Cac tap chat lien quan: Th du N,N-dimethylanilin (trong ampicillin hoac amoxicillin) bang sac ky kh.
H H C NH2 O H CO NH N COO Na H S

H H HO C NH2 O CO NH N H COO Na H S

Amoxicillin

Ampicillin

Kiem nghiem
nh lng

1. PHNG PHAP OXY HOA KH

Penicilin

phan huy

D-penicillamin + acid penaldic

2. PHNG PHAP HPLC 3. PHNG PHAP VI SINH VAT (Xac nh hoat lc cua khang sinh)

OC TNH VA TAI BIEN

Cac khang sinh nhom penicillin rat t oc, Tai bien chu yeu do d ng, D ng nhe gay nga, noi me ay D ng nang gay shock phan ve

PENICILLIN NHOM I
Penicillin thien nhien
H H CH2 CO HN N O H S CH3 CH3 COO R'

H2 O O C C NH H H N O H

S COO

Peni G

Peni V

Penicillin G (benzyl penicillin) Dang tac dung nhanh: Na/K benzyl penicillin Dang tac dung cham: procain PNC, benethamin PNC, benzathin PNC Penicillin V (phenoxy methyl penicillin)

PENICILLIN NHOM I

Penicillin ban tong hp

X

Ben trong moi trng acid, hap thu tot hn, hoat chat trong huyet thanh cao hn, T1/2 dai hn.

H CH CO N Z X O

H H S N H CH 3 CH2 COO

Z = N3 - ; X = H : azidocillin Z = OCH3 - ; X = Cl : clometocillin

T PNC-G: azidocillin, clometocillin

T PNC-V: pheneticillin, propicillin, phenbenicillin

H O CH CO N Z O

H H S N H CH 3 CH2 COO

Z = CH 3- : pheneticillin Z = C2 H5 - : propicillin Z = C6 H5 - : phenbennicillin

PENICILLIN NHOM I
Pho khang khuan Pho khang khuan hep, chu yeu tren gram (+):
Cau khuan gram (+): tu cau khong tiet

penicillinase, lien cau, phe cau

Cau khuan gram (-): lau cau (khuynh hng tang

MIC va xuat hien nhng chung e khang). va Borelia burgdorferi.

Xoan khuan: xoan khuan giang mai, leptospira Trc khuan gram (+): trc khuan gay benh bach

hau, benh than, listeria(viem mang nao), erysipelothrix (viem quang).

KHONG TAC DUNG TREN TRC KHUAN GRAM (-)

Meticillin, oxacillin, cloxacillin, dicloxacillin,

Pho hep gan giong penicillin nhom I, nhng co kha nang khang lai penicillinase do S. aureus tiet ra.

PENICILLIN NHOM II

CH3 H CO HN N O Meticillin H H S CH3 CH3 COO Na

CH3

PENICILLIN NHOM II Meticillin, oxacillin, cloxacillin, dicloxacillin,

X H C N Y O O isoxazolylpenicillin
X Y ------------------------------------------------------------Oxacillin (Bristopen) H H Cloxacillin (Orbenin) Cl H Dicloxacillin (Dicloxil) Cl Cl Fluocloxacillin (Floxapen) Cl F Chu y: s a thay the lam giam hoat tnh khang sinh

H S N H CH3 CH3 COO Na

C C

CO CH3

HN

Ph KK ca mt penicillin ph thuc vo: - Cu trc - Kh nng xuyn mng VK gram m -Tnh nhy cm vi betalactamse - i lc vi enzym mc tiu transpeptidase - Tc b bm ra ngai VK gram m M mm (trial and error) tm kim penicillin ph rng Mt lng ln cht tng ng c tng hp vi nhng thay i nhnh bn, vi nhng nhn xt SAR nh sau: - Nhm hydrophobic (peni G) tt trn gram + nhng khng tt trn gram _ - S gia tng trn gram m tm thy tt nht vi nhng nhm hydrophylic carbon alpha (iu ny c cho l tr gip nhng penicillin ny bng qua porin outer cell membrane ca VK gram m)
H CH2 CO HN N O H H S CH3 CH3 COO R'

H CH2 CO HN

H S N CH3 CH3 H COO R'

The tren C cua chc carboxamid (PNC- G): amin, hydroxyl, carboxylic, sulfonilic M rong hoat pho sang vi khuan gram am

PENICILLIN NHOM III

1945

Dch nuoi cay Cephalosporium acremonium

HOOC NH2 C NH O O penicillin N S COOH

(yeu hn peni G tren gramdng, nhng co tac ong tren gram am)

PENICILLIN NHOM Ampicillin

 Nhom III: gom co 2 phan nhom IIIA va III B: III-A: khong co nhom the tren amin (NH2): Ampicillin, Amoxicillin III-B: co nhom the tren amin (NH2): Azlocillin, Mezlocillin, Piperacillin

PNC NHOM III-A Ampicillin, Amoxicillin

- Bn vi acid
- Nhng nhy cm vi lactamse. - Hp thu km qua rut

2S,5R,6R)-6-[[(2R)-2-amino-2-phenylacetyl]amino]-3, 3-dimethyl-7-oxo4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

(2S,5R,6R)-6-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,

Pho khang khuan III-A

Ampicillin, Amoxicillin Pho cua penicillin G cong them mot so vi khuan gram am nh Haemophilus, Escherichia, Proteus mirabilis, Salmonella, Shigella.

Mot so vi khuan gay nhiem trung mac phai tai benh vien khong nhay cam vi nhom khang sinh nay: Enterobacter, Serratia, Proteus indol dng, Providencia, Bacillus pyocyanic.

PNC NHOM III-B

Azlocillin, Mezlocillin, Piperacillin

Tac ong tren cac mam e khang vi ampicillin nh: Klebsiella, Enterobacter, Serratia, Pseudomonas Piperacilin phoi hp vi aminosid hoac vi chat c che betalactamase

PENICILLIN NHOM IV (-carboxy-PNC)

Carbenicillin, ticarcillin, carindacillin
H H Ar C CO Z N O H Ar Z COO Na HN COO H S

H O C C HN SO3H O

H H S N COO Na

Sulbenicillin
Na

Carbenicillin

Ben ve mat hoa hoc Hoat tnh KK tng t cac -carboxy-PNC

Carindacillin

Z=phenyl : Carfecillin
Na S

Ticarcillin

- Hoat tnh tren trc khuan mu xanh - ong van vi aminosid - Ticarcillin hoat tnh 2 lan manh hn carbenicillin.

PENICILLIN NHOM VI (Amidino-PNC)

H N CH N N O Amidinopenicillin H H S CH3 CH3 COO R' R' Na+ CH2 O CO C(CH3)3 (HCl) Te n ho a ho c Mecillinam Pivmecillinam (Selexid)

(nhn azepin gn trn lin kt amidine)

Pho KK hep, tap trung chu yeu tren VK gram am. Rat nhay cam: Escherichia coli. Nhay cam: Yersinia, Salmonella, Shigella,

N CH NH azepan-1-ylmethanimine

Enterobacter, Citrobacter,

Klebsiella (khong san xuat hoac san xuat yeu penicillinase). Khong e khang cheo vi ampicillin

CHAT C CHE -LACTAMASE

AI CNG Nhieu loai vi khuan co kha nang tiet ra cac enzym beta lactamase phan huy cac khang sinh ho beta lactamine. S san sinh cac enzym nay co the la t nhien hay tiep nhan c. Men beta lactamase bao gom penicilinase va cephalosporinase.

C CHE TAC ONG

Chat c che beta lactamase + cac penicillin: m rong pho khang khuan cua nhng chat nay len cac vi khuan tiet men penicillinase. Sau khi gan vi men penicillinase, cac chat nay se b phan huy.

Acid clavuclanic (suicide inhibitor)

H H H N O H O C H COOH CH2 OH

Thu c t Streptomyces clavuligerus

Cau truc clavam (oxapenam) c s dung dang muoi kali clavuclanat

Cac phoi hp: acid clavuclanic amoxicillin,

acid clavuclanic ticarcilin clavulanate meropenem (ang nghin cu)

Pho khang khuan cua phoi hp B. clavuclanic amoxicillin Cai thien tren nhng mam nhay cam san xuat beta lactamase nh Neiserria gonorhoeae, Haemophilus, E. coli, Salmonella. A. clavuclanic ticarcillin Phoi hp nay gia tang tac ong tren Staphylococcus (95% Streptococcus nhay cam vi phoi hp acid clavuclanic ticarcillin so vi 49% neu ch s dung mot mnh ticarcillin).

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

H H O S OCH H 3 N CH 3 O H COOH

Dan chat cua penam, ban tong hp t 6 APA

Cau truc tng t penicillin nhng khong co nhom the C6 (mat C*), S v tr 4 c oxy hoa thanh SO2,

Cau hnh C2 va C5 giong penicillin

Phoi hp sulbactam-ampicillin

Sultamicillin
NH 2 H N N O O Sultamicillin S CH3 CH 3 O H3 C H 3C O O O S O N O

- Dan chat este i t sulbactam va ampicillin

- Hoat tnh tren cau khuan gram dng, gram am; trc khuan gram dng, gram am

- c dung trong tai-mui-hong, ho hap, sinh duc, da tren nhng mam nhay cam

Tazobactam
H H O N N S OCH H 2 N N CH 3 O H COOH

Dan chat cua sulbactam ma mot nhom methyl mang nhom the triazolyl
Chat c che betalactamase khong thuan nghch pho rong S dung di dang phoi hp tazobactam - piperacillin

CARBAPENEM
HO H3 C N O Carbapenem N O S COOH NH2

Thienamycin (1977)

Thienamycin :

- trch t moi trng nuoi cay Streptomyces cattleya. - hoat tnh khang khuan rong - hoat tnh tren Pseudomonas - khang lai -lactamase

NH2

NH CH NH

Plays a role in lactamase resistance

H OH H Me N O S CO2

Thienamycin R = NH3 Imipenem R = NH-CH=NH

Double bond leading to high ring strain and increase in lactam reactivity

IMIPENEM
HO H3C N O S COOH HO H3C benzyl formimidat N O S COOH Imipenem NH NH

NH 2

Thienamycin (1977)

Acid [hydroxy-1 ethyl (R) ] 6[[(iminomethylamino-2) ethyl]thio]-3-oxo-7-aza-1bicyclo [3.2.0]hepten-2 carboxylic-2 (5R,6S).

IMIPENEM
HO H 3C N O
Pho khang khuan

NH NH S COOH

Ben vng vi men beta lactamase, pho khang khuan rat rong, bao gom:

-Cau khuan gram dng: Staphylococcus nhay meticillin (Staphylococcus khang meticillin e khang vi imipenem), Strepococcus (ke ca nhom D), Pneumococcus, Enterococcus.
-Cau khuan gram am: Neisseria

-Trc khuan gram dng: Clostridium, Listeria monocytogenes

- Trc khuan gram am: H. influenzae, E. coli, Klebsiella, Proteus mirabilis, Enterobacter, Citrobacter, Serratia, Proteus vulgaris, Bacteroides fragilis, Acinetobacter, P. aeruginosae.

IMIPENEM
HO H 3C N O
- IV cham.

NH NH S COOH
khi s dung thng

- De b phan huy bi dehydropeptidase ong than

ket hp imipenem vi cilastin (chat c che enzym dehydropeptidase) e gii han s chuyen hoa nay.

cilastin

4-Methyl carbapenem Bn hn i vi s thy gii ca dehydropeptidase

H OH H Me N O H N C S CO2

CH3

O
1 R N R2

Meropenem R 1= R 2 = Me Ertapenem R 1= H; R 2 = CO2

HO S CO 2H Imipenem NH HN N O

Ni chung, carbapenem c ph khng khun rng nht trong tt c cc KS lactames.

HO S CO 2H Imipenem

NH HN N

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 . A series of 4-methyl carbapenems having structural similarity to ME1036 showed potent activities against MRSA and PRSP, as well as against the gram-negative organism ampicillin-resistant, -lactamase-negative Haemophilus influenzae

HO S CO 2H Imipenem

NH HN N

PZ-601 (Razupenem). PZ-601 (formerly known as SMP601; 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.