ANTIBIOTICE

BETALACTAMINE Peniciline Cefalosporine Inhibitori ai beta-lactamazelor Carbapeneme Peneme Monobactame Nocardicine Tribactame (Trineme) ANTIBIOTICE AMINOGLICOZIDICE cu aglicon streptidinic: Streptomicine cu aglicon dezoxistreptaminic: Neomicina Framicetina Paromomicina Ribostamicina Kanamicina Amikacina Arbekacina Bekanamicina Dibekacina Tobramicina Spectinomicina Hygromicina B Paromomicina Gentamicina Netilmicina Sisomicina Isepamicina TETRACICLINE Tetraciclina Oxitetraciclina Doxiciclina Clortetraciclina Clomociclina Demeclociclina Limeciclina Meclociclina Metaciclina Minociclina Penimepiciclina Rolitetraciclina

 MACROLIDE NEPOLIENICE

FALSE MACROLIDE Rifamicina SV Rifamida Rifazina Rifampicina

Eritromicina
Azitromicina Spiramicina Midecamicina Oleandomicina Roxitromicina Josamicina Troleandomicina Claritromicina Miocamicina Rokitamicina Diritromicina Fluritromicina Telitromicina Cetromicina

 AMFENICOLI

LINCOSAMIDE

STREPTOGRAMINE

Cloramfenicol Azidamfenicol Tiamfenicol Florfenicol

Clindamicina Lincomicina

Pristinamicina Quinupristina Dalfopristina Virginiamicina

ANTIBIOTICE CU STRUCTUR POLIPEPTIDIC

Polimixine Colistina Bacitracina

OXAZOLIDINONE
Cicloserina Terizidona

PLEUROMUTILINE
Retapamulina Tiamulina Valnemulina

N O
azetidin-2-ona

CLASIFICARE:
betalactamine biciclice condensate (4,5):

- penicilinele: peniciline naturale, peniciline cu actiune prelungita, peniciline de semisinteza (peniciline stabile n mediu acid, peniciline stabile fa de penicilinaze, peniciline cu spectru larg de actiune (aminopeniciline, amidinopeniciline, -carboxipeniciline, ureidopeniciline));

-inhibitorii beta-lactamazelor;
-penemele (ciclul betalactamic condensat cu un ciclu tiazolinic); -carbapeneme (ciclul betalactamic condensat cu un ciclu 2,3-dihidropirolic); betalactamine biciclice condensate (4,6):

-cefalosporinele i cefamicinele (ciclul betalactamic condensat cu un ciclu dihidrotiazinic);

-oxacefemele (ciclul betalactamic condensat cu un ciclu dihidrooxazinic); -carbacefemele (atomul de sulf din nucleul de baz grupare metilen);

 betalactamine monociclice: -monobactamele; -nocardicinele; betalactamine triciclice: -tribactame (trineme) (ciclul betalactamic condensat cu un sistem biciclic pirolino - ciclohexanic).

N-acetilglucozamina (NAG) acid N-acetilmuramic (NAM)

Structura peptidoglicanului

 Masele moleculare, afinitatea [i distribu]ia proteinelor fixatoare de penicilin\ `n Escherichia coli (dup\ Spratt (1977))
Proteina 1 2 3 4 5 6 Masa molecular\ 91000 66000 60000 49000 42000 40000 Fixarea penicilinei (%) 8,1 0,7 1,9 4,0 64,7 20,6 Molecule/celul\ 230 20 50 110 1800 570

CH3 H H S R C NH C C C CH3
B A

O C

CH COOH

Sir Alexander Fleming (1881-1955)

Sir Howard Florey (1898-1968)

 NOMENCLATURA

CH3 H H S R C NH C6 5C 4 3 C CH3 O C
7

CH COOH

acizi 3, 3-dimetil-7-oxo-6-R-acilamino-4-tia-1-azabiciclo3.2.0heptan-2-carboxilici:

S O N

H2N O N

CH3 CH3 COOH

nucleu penam

acid 6-amino-penicilanic
acizi R-acil-amino-penicilanici.

acizi 6-acilamino-3, 3dimetilpenam-2-carboxilici.

O R C NH O

H H S
6 7 5 4 3 1 2

CH3 CH3 COOH

H
+

CH3 H H S R C NH C C C CH3 O C N CH COOH Penicilina

H
2S:5R:6R:

COOH CH NH CH COOH N R O O HS C CH3 CH3 S N R N C(CH3)2 COOH HO

-

H2O Acid penilic

-

Acid penicilenic H2O

CO2 S C(CH3)2 COOH

S R CONH C CH NH CH COOH COOH HS C CH3 CH3 Acid penamaldic R CONH CH COOH N H

C(CH3)2 COOH

R CONH CH2 N H

Acid peniciloic

Acid peniloic

CH3 H3C C CH COOH + R CONH CH CHO HS NH2 Penicilamina COOH Acid penaldic
-

CO2

R CONH CH2

CHO

Peniciloaldehida

CH3 H H S R C NH C C C CH3 O C N CH COOH

NH2OH (NaOH)

CH3 H H S R C NH C C C CH3 O C N H NH OH Acid hidroxamic CH COOH

O R C

CH3 H H S NH C C C CH3 O C N CH COOH

O R'NH2 R C

CH3 H H S NH C C C CH3
-

CH COOH

O
2

+NH

R'

O R C

H H S NH C C C C
O NH

CH3 CH3 COOH

N H

CH

R' Peniciloilamida

CH3 H H S R C NH C C C CH3 O C N (..) CH COO Me

OBINEREA PENICILINELOR Obinerea penicilinelor prin biosintez ACV sintetaz (EC 6.3.2.26)
-

2+

3 ATP + acid L-2-aminohexandioic + L-cisteina + D-valina + H2O = 3 AMP + 3 difosfat + N-L-5amino-5-carboxipentanoil-L-cisteinil-D-valina. isopenicilina-N sintaza (EC 1.21.3.1) N-L-5-amino-5-carboxipentanoil-L-cisteinil-D-valina + O2 = isopenicilina N + 2 H2O

isopenicilina N N-aciltransferaza (EC 2.3.1.164) isopenicilina-N epimeraza (EC 5.1.1.17)

Acil-CoA + isopenicilina N + H2O = CoA + penicilina + acid L-2-aminohexandioic; Isopenicilina N penicilina N.

penicilin-amidaza (EC 3.5.1.11)

Penicilina + H2O = acid carboxilic + 6-APA

H H2N HOOC acid L-2-aminoadipic (acid L-2-aminohexandioic) H C (CH2)3 COOH + HOOC L-cisteina H2N H C CH2 S H + H2N H C CH3 CH3 C COOH D-valina

3 ATP + H2O EC.6.3.2.26 3 AMP + 3 PP H2N HOOC O H C (CH2)3 CO

H N

S H H CH CH2 3 CH 3 NH H COOH

EC 1.21.3.1 O2 - 2 H2O

H2N HOOC

H C (CH2)3 CO

H N

H H S N H CH3 CH3 COOH

O isopenicilina N RCO CoA + H2O EC 2.3.1.164

N-[L-5-amino-5-carboxipentanoil]-L-cisteinil-D-valina

EC 5.1.1.17 CoA + acid L-2-aminohexandioic H H2N

H2N

H H S N H CH3 CH3 COOH EC 3.5.1.11

R CO

H N

H H S N H CH3 CH3 COOH HOOC

(CH2)3

CO

H N

H H S N H CH3 CH3 COOH

O R COOH H2O

O penicilina N

peniciline de semisinteza

penicilina F, R = C2H5CH CHCH2 penicilina G, R = C6H5CH2 penicilina K, R = CH3(CH2)6 penicilina O, R = CH2 CHCH2SCH2 penicilina V, R =C6H5OCH2 penicilina X, R =4-HO C6H4 CH2 penicilina T, R = 4 H2N C6H4 CH2

 Obinerea penicilinelor prin semisintez

O C6H5OCH2

CH3 H H S C NH C C C CH3 O C N CH COOH

OH C6H5OCH2

CH3 H H S C N C C C CH3 O C N CH COOH

Cl 1. ClSi(CH3)3 2. PCl5 C6H5OCH2

CH3 H H S C N C C C CH3 O C N CH COOSi(CH3)3

(n) C4H9OH

OC4H9 C6H5OCH2

CH3 H H S C N C C C CH3 O C N CH COOSi(CH3)3

H2O

CH3 H H S H2N C C C CH3 O C N CH COOH 6-APA

-Acilarea cu cloruri acide

CH3 H H S H2N C C C CH3 O C N
+

R COCl +

N(C2H5)3
-

CH3 H H S R C NH C C C CH3 O C N CH COOH

CH COOH NH(C2H5)3Cl

-Acilarea cu anhidride acide

O R C O + R C O CH3 H H S H2N C C C CH3 O C N CH COOH _ RCOOH CH3 H H S R C NH C C C CH3 O C N CH COOH O

-Acilarea cu anhidride mixte

O RCOOH + Cl C OR'
CH3 H H S R C NH C C C CH3 _ CO _
2

O R C O + R' O C O

CH3 H H S H2N C C C CH3 O C N CH COOH R'OH

O C N

CH COOH

-Acilarea prin intermediul N,N-diciclohexilcarbodiimidei:

RCOOH +

N C N

NH C N O C O R

CH3 H H S H2N C C C CH3 O C N CH COOH

CH3 H H S R C NH C C C CH3 O C N CH COOH

N C NH OH

NH C NH O

 Obinerea penicilinelor prin sintez total

O NCHCHO COOC(CH3)3 O t-butil alfa-ftalimidomalon-aldehida O N O CH CO N H S CH3 CH3 COOH H2N NH2 HCl H2N CH CO N H OC(CH3)3 S CH3 CH3 . HCl COOH D-penicilamina clorhidrat + (CH3)2C SH CHCOOH . HCl NH2

OC(CH3)3

C 6H5OCH2COCl (C 2H5)3N

C 6H5OCH2CONH

CH CO N H

CH3 CH3 COOH

HCl piridina

OC(CH3)3 S CH3 CH3 COOH KOH

N C6H11 C N C6H11

C6H5OCH2CONH

CH CO N H OH

C6H5OCH2CONH O

CH N

CH3 CH3 COOK

 IDENTIFICARE I DOZARE

CH3 H H S R C NH C C C CH3 O C N CH COOH

+ NH2OH (NaOH)

CH3 H H S R C NH C C C CH3 O C N H CH COOH

FeCl3

NH OH CH3 H H S R C NH C C C CH3 O C Fe/3 NH O complex violet N H CH COOH O

CH3 H H S R C NH C C C CH3 O C N CH COOH

CH3 H
+

HS C CH3 H2N C H COOH D-penicilamina

O + R C NH CH CHO COOH acid penaldic CO2

O R C NH CH2 CHO peniloaldehida CH3 HS C CH3 H2N C H COOH D-penicilamina + OH O ninhidrina O hidrindantina O OH O CH3 OH + NH3 + CO2 + HS C CH3 CHO

O OH + 2 NH3 + HO OH O ninhidrina

O N O

- 3H2O O hidrindantina

ONH4

colorant indaminic (violet)

CH3 H H S R C NH C C C CH3 O C N CH COOH

CH3 H H S R C NH C C C CH3 HOOC N CH COOH H Acid peniciloic

CH3 HS C CH3 CH COOH NH2 + R CO NH CH CHO COOH Acid penaldic I2 H2O

Penicilamina 3 I2 3 H2O CH3 HO3S C CH3 CH COOH NH2

R CO NH CH COOH COOH Acid penaldioic

Acid penicilaminosulfonic

 BENZILPENICILINA POTASIC BENZYLPENICILLINUM KALICUM (DCI) (FR X)

O K
+

CH2

C NH N O

CH3 CH3 COO

-

(2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenilacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilat de potasiu

Sinonime: Penicilina G potasic, Penicilina II potasic, Fenilacetilpenin potasic.

PF: PENICILINA G POTASIC (SC Antibiotice SA Iasi) - pulbere steril injectabil (400.000 UI, 1.000.000 UI); PFIZERPEN (Pfizer, S.U.A.) - pulbere steril injectabil (5.000.000 UI).

 BENZILPENICILINA SODIC
BENZYLPENICILLINUM NATRICUM (DCI) (FR X)
O Na
+

CH2

C NH N O

CH3 CH3 COO

-

(2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenilacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilat de sodiu

Sinonime: Penicilina G sodic, Penicilina II sodic, Fenilacetilpenin sodic.

PF: PENICILINA G SODIC (SC Antibiotice SA Iasi) - pulbere steril injectabil (400.000 UI, 1 mil. UI);
CRYSTAPEN (Brittania Pharmaceuticals Ltd., U.K.)

 FENOXIMETILPENICILINA
PHENOXYMETHYLPENICILLINUM (DCI) (FRX)

O O CH2 C NH N O

CH3 CH3 COOH

Acid (2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenoxiacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilic

Sinonime: Penicilina V; Fenomicilina.

CH3 H H S H2N C C C CH3 O C N CH COOH Clorura acidului fenoxiacetic O O CH2 C NH N O Fenoximetilpenicilina S CH3 CH3 COOH 6-APA O + O CH2 C Cl N(C2H5)3 -+NH(C2H5)3Cl-

 PF: PENICILINA V (Antibiotice SA, Armedica, Europharm SA Romania) comprimate a 400000

UI si 1 milion UI / cp. OSPEN (Biochemie Austria) comprimate filmate a 500000, 1 milion si 1,5 milioane UI / cp.; sirop 400000 UI / 5 ml; PENHEXAL SAFT (Hexal AG Germania) pulbere pentru soluie injectabil (400000 UI / 5 ml); CLIACIL (Hoechst Marion Roussel Turcia) comprimate filmate a 1,2 milioane UI / cp., sirop 400000 UI / 5 ml, pulbere suspendabil 300000 UI / 5 ml. PEN V (Genericon - Austria) - comprimate a 1 milion si 1,5 milioane UI / cp.

PENICILINE CU ACIUNE PRELUNGIT (DEPOZIT, DEPOT, RETARD)

COOH COOH

SO 2N(C3H7)2 Acid p-(di-n-propilsulfamoil)-benzoic Probenecid

NHSO 2 CH2 C6H5 Acid N-benzilsulfonil-p-aminobenzoic Caronamid

 PROCAIN BENZILPENICILINA BENZYLPENICILLINUM PROCAINICUM (DCI)

+

C2H5 C2H5

COOCH2CH2 NH O CH2 C NH N O S CH3 CH3 COO

-

H2O

Sarea acidului (2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenilacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilic cu 4-aminobenzoatul de 2-dietil-aminoetil

NH2

Sinonime: Benzilpenicilina procainic; procain penicilina G.

C2H5 COOCH2CH2 N C2H5 NaNO2 + 2 HCl - NaCl - H2O

C2H5 COOCH2CH2 N C2H5

NaO + NaOH - NaCl - H2O

NH2

N N] Cl

C2H5 COOCH2CH2 N C2H5

N N ONa

PF. EFITARD (Antibiotice SA Romania) - flacoane de 400000 UI, din care 300000 UI benzilpenicilina procainica si 100000 UI benzilpenicilina K si flacoane de 800000 UI, din care 600.000

UI benzilpenicilina procainica si 200.000 UI benzilpenicilina K;

FORTEPEN (Biochemie - Austria); WYCILLIN (Wyeth Ayerst USA).

 BENZATIN BENZILPENICILINA BENZATHINI BENZYLPENICILLINUM (DCI)

O CH2 C NH N O

CH3 CH3 COO

-

CH2 CH2 + + H N CH2CH2 N H 2 H H

Sarea acidului (2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenilacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilic cu N, N-dibenziletilendiamina

O 2 K
+

Sinonime: Benzetacil; DBED-penicilina.

CH2

C NH N O

CH3 CH3 COO

-

CH2 CH2 + + H N CH2CH2 N H H H

(CH3COO )2

O CH2
-2 CH3COOK

C NH N O

CH3 CH3 COO

-

CH2 CH2 + + H N CH2CH2 N H 2 H H

 PF. MOLDAMIN (Antibiotice SA Romnia) - pulbere sterila, de uz parenteral (600000; 1,2 mil. sau 2,4 mil. UI); RETARPEN (Biochemie Austria) ; EXTENCILLINE (Specia Frana).

BENETAMIN BENZILPENICILINA BENETHAMINI BENZYLPENICILLINUM (DCI)

O CH2 C NH O N S CH3 CH3 COO
+

CH2

C6H5 C6H5

H2N CH2CH2

Sarea acidului (2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenilacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilic cu N-benzil-N-feniletil-amina

PF: ATRALMICINA (Atral, Portugalia) pulbere pentru suspensie injectabil (600000 UI).

 CLEMIZOL BENZILPENICILINA CLEMIZOL BENZILPENICILLINUM (DCI)

O CH2 C NH O N CH3 CH3 COO
-

N N CH2

H + N CH2

Cl

Sarea acidului (2S, 5R, 6R)-3,3-dimetil-7-oxo-6-(fenilacetamido)-4-tia-1-azabiciclo 3. 2. 0 heptan-2-carboxilic cu 1-p-clorbenzil-2-pirolidil-metil-benzimidazol-ul