KHANG SINH AMINOSID

AI CNG
Aminoglycosid: heterosid thien nhien (genin: aminocyclitol + nhieu ose, t nhat 1 ose amin) Streptomycin (1943) do S.A Waksman (USA, Nobel 1952) tm ra . Neomycin (1949), kanamycin (1957), gentamicin (1964). Tobramycin, sisomicin va cac aminosid ban tong hp c tm thay trong nhng nam 70.

Tong cong khoang hn 50 aminosid c tm thay, khoang 10 - 12 chat c s dung trong ieu tr.

CAU TRUC
NH
4

Lien ket glycosidic

C
3 NH2 2 3 5

HN

HO HO
5

NH2 2 OH 6 HN 1 OH

NH C NH2

HO HO

R
6 1 NH2

OH

streptidin H3C
O

D-streptamin : R = OH Desoxy-2-streptamin : R = H NH2 HC CH2NH2

HO H2C H2N OH garosamin OH

o
OH

NH2 sisosamin

OH

purpurosamin

Genin: Streptidin: streptomycin Streptamin: spectinomycin

Cac ose: D-glucosamin-2, D-glucosamin-3, Garosamin, Purpurosamin, Sisosamin,

Desoxy2 streptamin : cac aminosid khac

Fortamin : fortimicin

IEU CHE
Aminosid thien nhien
Aminosid t Streptomyces co tiep v ng MYCIN Aminosid t Micromonospora co tiep v ng MICIN. - Streptomycin t Streptomyces griseus. - Gentamicin t Micromonospora purpurea. Aminosid ban tong hp

PHAN LOAI AMINOSID

Genin

1,3-Diamino cyclitol

1,4Diamino cyclitol Fortamin Fortamicin

Streptamin Thien nhien Spectinomycin

Streptidin Streptomycin

2-Desoxy -streptamin (the 4, 5) Neomycin Paramomycin Lividomycin Ribostamycin (*) (the 4,6) Kanamycin Gentamicin Tobramycin Sisomicin Amikacin Dibekacin Netilmicin

Ban tong hp

Dihydro streptomycin (*)

Dactimicin

(*): rat oc, khong dung tiem, nhng co the uong khi muon co tac ong tai cho.

TNH CHAT LY HOA

Kanamycin A, R=OH Kanamycin B, R=NH2

Nhom NH2 va OH Nhom amin va guanidin aminosid co tnh base (pka 7,5-8), thng c s dung dang muoi. Dang muoi: thng la muoi sulfat, hao am, rat tan trong nc, khong tan trong alcol va dm hu c. Dung dch pH trung tnh ben vi nhiet, thuy giai cham trong moi trng acid.

KIEM NGHIEM
Kanamycin A, R=OH Kanamycin B, R=NH2

nh tnh: - Phan ng vi ninhydrin

- Phan ng vi dihydroxy-2,7-naphtalen/H2SO4
- Sac ky lp mong - Phan ng vi acid picric

- Phan ng cua ion sulfat

- Ph UV ?

Gentamicin Sulphate

IDENTIFICATION First identification C, D. Second identification A, B, D. A. Dissolve about 10 mg in 1 ml of water R and add 5 ml of a 400 g/l solution of sulphuric acid R. Heat on a water-bath for 100 min, cool and dilute to 25 ml with water R. Examined between 240 nm and 330 nm (2.2.25), the solution shows no absorption maximum. B. Thin-layer chromatography (2.2.27). .. DetectionSpray with ninhydrin solution R1 and heat at 110 C for 5 min. C. Examine the chromatograms obtained in the test for composition. ResultsThe chromatogram obtained with the test solution shows 5 principal peaks having the same retention times as the 5 principal peaks in the chromatogram obtained with reference solution (a). D. It gives reaction (a) of sulphates (2.3.1).

Kanamycin Sulphate

IDENTIFICATION A. Examine by thin-layer chromatography (2.2.27 .. Dry the plate in a current of warm air and spray with a mixture of equal volumes of a 2 g/l solution of dihydroxynaphthalene R in alcohol R and a 460 g/l solution of sulphuric acid R. B. Dissolve 0.5 g in 10 ml of water R. Add 10 ml of picric acid solution R. Initiate crystallisation if necessary by scratching the wall of the tube with a glass rod and allow to stand. Collect the crystals, wash with 20 ml of water R and filter. Dry at 100 C. The crystals melt (2.2.14) at about 235 C, with decomposition. C. Dissolve about 50 mg in 2 ml of water R. Add 1 ml of a 10 g/l solution of ninhydrin R and heat for a few minutes on a water-bath. A violet colour develops. D. It gives the reactions of sulphates (2.3.1).

KIEM NGHIEM
Kanamycin A, R=OH Kanamycin B, R=NH2

nh tnh: - Phan ng vi ninhydrin

- Phan ng vi dihydroxy-2,7-naphtalen/H2SO4
- Sac ky lp mong - Phan ng vi acid picric

- Phan ng cua ion sulfat

- Ph UV ? - Ph IR
(amikacin, spectinomycin)

Amikacin

OH H3C - NH H O H O CH3

HO

O H OH O NH -CH3

KIEM NGHIEM
Kanamycin A, R=OH Kanamycin B, R=NH2

nh tnh: - Phan ng vi ninhydrin

- Phan ng vi dihydroxy-2,7-naphtalen/H2SO4
- Sac ky lp mong - Phan ng vi acid picric

- Phan ng cua ion sulfat

- Ph UV ? - Ph IR (amikacin, spectinomycin) - Ph 1H-NMR
(tobramycin)

Nuclear magnetic resonance spectrometry: Preparation 100 g/l solution in deuterium oxide R.

Comparison 100 g/l solution of tobramycin CRS in deuterium oxide R.

H2 N O HO HO H2 N

O NH2 HO O NH2 O

NH 2

HO OH Tobramycin

ChemNMR 1H Estimation

Tobramycin
2.0 H 2N 3.91 2.91;2.66 2.0 5.18 NH2 2.89 2.00;1.76 3.05 OH O 2.09;1.85 2.89 4.81 NH 3.10 3.81 2 NH2 2.0 3.10 3.79;3.54 HO 4.78 HO 3.76 4.81 O O 2.0 5.03 3.55 NH 2 3.88 OH 2.89 4.81 OH 3.32

Estimation quality is indicated by color: good, medium, rough

3 PPM

Kanamycin A, R=OH Kanamycin B, R=NH2

KTK:

- Kiem oc tnh bat thng (th tren chuot)

- pH, nang suat quay cc, - Tap chat lien quan (Td: kim TK streptomycin B trong chuyn lun streptomycin sulfat) nh lng: Phng phap sinh hoc HPLC

C CHE TAC ONG

Tac ong tren 30S

LIEN QUAN CAU TRUC VA TAC ONG

Kanamycin A, R=OH Kanamycin B, R=NH2

Nhom amino trong phan t ng

So lng nhom amino trong phan t aminoglycosid anh hng trc tiep en kha nang tac dung cua khang sinh.
1

Nhom OH

1- Antimicrobial Agents and Chemotherapy. 1973, 4(4): 402-409.

PHO KHANG KHUAN

(Pho lam sang tng t quinolon)

Pho khang khuan: rong, chu yeu la gram am, ai kh (Enterobacterie) va trc khuan gram dng Tac ong tot tren Staphylococcus aureus ke ca chung tiet penicillinase, tren Neisseria miningitidis va Gonorrhoea. Streptomycin ac biet hoat tnh tren Mycobacterie. Kanamycin va amikacin co tac ong nay nhng kem. Paramomycin the hien hoat tnh tren protozoa.

Co s ong van vi cac khang sinh khac ( -lactam, polypeptid, quinolon, vancomycin, fosfomycin).

ROCHN

CO 2H NH ROCHN O N CO2 H sugar O HN HO

Gentamicin C-2a +
(active) O

NH 2 O sugar

betalactam (active)

(inactive)

E KHANG

1, 2

Bat nguon t 1 trong 3 c che sau: ot bien tren ribosome

Kanamycin A, R=OH Kanamycin B, R=NH2

S ot bien xay ra tai ni ket hp vi thuoc

Giam tnh tham KS qua mang vi khuan

Thuoc khong vao c ben trong, khong the tng tac vi ribosome

Enzymes thoai hoa aminoglycosides

Aminoglycosides co the b bat hoat bi phosphorylation, acetylation, or adenylation
1- Drugs. 2001. 61(6): 713-721 2- Current Drug Targets Infectious Disorders. 2002, 2: 143-1604

- AAC: aminoglycoside acetylase - APH: aminoglycoside phosphorylase - ANT: aminoglycoside nucleotide transferase
NH 2 Ad Phos HO X Ac O H Ac Ac NHR O O H2 N Ac Tobramycin (X=H, Y=NH2 , R=H) Kanamycin A (X=OH, Y=OH, R=H) Amikacin (X=Y=OH, R=COCHOHCH2 CH2 NH 2) (Ad: adenylation; Ac: acetylation; Phos: phosphorylation) OH Ad

Y O H2 N HO HO HO

Gii quyt vn khng?

OC TNH

oc tnh tai:
Aminosids tac ong tren cap th 8 cua than kinh so tien nh: streptomycin oc tai: amikacin ca hai: gentamicin, tobramycin, dibekacin; Netilmicin tng oi t oc vi tai. oc tnh than:

Cac aminosid co the gay hoai t ong uon gan va lam giam s loc tieu cau than.

Aminosids: KS phu thuoc nong o va co tac dung hau khang sinh ong van vi beta-lactam, polypeptid, quinolon, vancomycin.

CH NH Ch nh Toan than, cuc bo Khang sinh Gentamicin, Tobramycin, Sisomicin, Dibekacin. Netilmicin, Amikacin, S dung tiem bap

Nhiem trung tieu hoa, dung tai cho Lao, d. hach Lau cau

Neomycin, Framycetin Paramomycin, Dihydrostreptomycin Streptomycin Spectinomycin

uong, dung ngoai uong tiem bap tiem bap

AMINOSID CO GENIN STREPTIDIN Streptomycin

Ad.; Phos.

Dng mui bn /dd nc pH= 3-7

Phan ng do nhom streptidin: - phn ng Sakaguchi

C. Dissolve 0.1 g in 2 ml of water R , add 1 ml of a-naphthol solution R and 2 ml of a mixture of equal volumes of strong sodium hypochlorite solution R and water R. A red colour develops BP 2007

Dng mui bn /dd nc pH= 3-7

Phan ng do nhom streptoza: Phan ng vi kiem, streptoza chuyen thanh maltol, chat nay tao phc mau tm ben vi Fe3+. Chc hydroxy-aldehyd: DD streptomycin sulphat tiet trung bang ultrafiltration.

R 1O O H

CH3

OR H OH CHO

OH

H OR2 R O H O OH
1

H OR2 R O H O OH
1

CH 3O

H3 C

OH

- R2 OH

R 1O

H OH OH

R1O

H H O OH

O H3 C

O H3 C

- R1 OH

O H3 C

O OH

O H3 C

O O Fe 3

nh lng: o quang, pp vi sinh vat

R CHO NH 2 HN + H+ N H - H2 O N H

HN

R CH N

Cl

9-hydrazinoacridin HCl

hydrazon phat quang

nh lng bng php o hynh quang streptomycin sulphat trong nc tiu v trong dch sinh hc khc.

Pho khang khuan

Proteus, Shigella
Tr lao, khang sinh nay mam trong danh muc thuoc thiet yeu cua WHO va la khang sinh chon la chong lai benh dch hach. S dung trong dc thc vat hoc va trong thu y e chong lai cac benh nhiem trung. oc tnh tren than yeu nhng phai chu y en oc tnh tai.

Dihydrostreptomycin

Streptomycin

Streptomycin B= Mannosido streptomycin

AMINOSID CO GENIN 2-DESOXY-STREPTAMIN Kanamycin (kanamycin A)

Kanamycin, gentamicin, neomycin, paramomycin:

ben ve mat hoa hoc. Co the un trong dd acid hoac kiem ma khong mat hoat tnh. Chu ng nhiet trong autoclavve.

O-phosphoryl hoa N-acetyl hoa

Ly trch t moi trng nuoi Streptomyces kanamyceticus

** Kim TK tp kanamycin B (c tnh cao)

AMINOSID CO GENIN DESOXY-2-STREPTIDIN

Kanamycin

Yeu hn gentamicin va tobramycin, Khong tac ong Pseudomonas (gay nhiem trung c hoi trong bong, phoi, ng tieu)

Nhieu mam gram am va trc khuan Koch e khang

oc tnh tng oi t hn cac aminosid khac. Thay bang amikacin (BTH, t b e khang hn).
( Tiem rat au)

AMINOSID CO GENIN DESOXY-2-STREPTAMIN

Gentamicin

Hm lng ca mi thnh phn c xc nh bng HPLC.

Mixture of the sulphates of antimicrobial substances produced by Micromonospora purpurea, the main components being gentamicins C1, C1a, C2, C2a and C2b.

AMINOSID CO GENIN DESOXY-2-STREPTAMIN

Gentamicin

S dung trong ieu tr la gentamicin C, dang sulfat Pseudomonas va Serratia nhay cam ac biet vi gentamicin. Theo doi ham lng trong huyet tng e giam nguy c oc tnh. T le toi u trong huyet tng phai di 10 g/ml.

AMINOSID CO GENIN DESOXY-2-STREPTAMIN Tobramycin

NH2 O Ac H Ac Ad Phos HO X Ac Y O H 2N HO HO HO H 2N Ac Tobramycin (X=H, Y=NH 2, R=H) Kanamycin B (X=OH, Y=OH, R=H) Amikacin (X=Y=OH, R=COCHOHCH 2CH 2NH2 ) O O OH Ad

NHR

Tobramycin ly trch t Streptomyces tenebrarius, hoac ban tong hp t kanamycin B (dseoxy 3 kanamycin B).

t oc tnh hn Gentamicin. Tr Pseudomonas e khang gentamicin.

AMINOSID BAN TONG HP

Aminosid ban tong hp ra i nham: giam oc tnh cua aminosid thien nhien (cha thc hien c) tm nhng aminosid khang lai vi cac enzym vo hoat. Mot so dan chat ban tong hp a c a vao s dung vi li iem lam giam s e khang cua vi khuan.

Amikacin, Netilmicin, Dibekacin, Arbekacin

AMINOSID BAN TONG HP

AMIKACIN

4'

6' H2C NH2

5' 2'

O
1'

HO HO
3'

OH O
4

Kanamycin A: R = H
NH2 2 3 5 6 1 NH R

Amikacin :
OH

HO
6"

R = CO

C
H

(CH2)2NH2

HO

4"

CH2OH
2" 3"

O
1"

H2N

OH

- S acyl hoa gay can tr ve mat khong gian

- Lam tang tnh a lipid cua phan t

Mot so VK e khang do tiet enzym tac ong len 4 va 6cua cac phan t ng

AMIKACIN

ieu tr :
Mycobacterium tuberculosis Yersinia tularensis (viem da day-ruot cap..) Pseudomonas aeruginosae (e khang vi nhng tac nhan
khac)

AMINOSID BAN TONG HP

Acyl hoa dibekacin bang hydroxy amino butyric v tr 1

Arbekacin

arbekacin = habekacin = 1-N-((S)-4amino-2-hydroxybutyryl)dibekacin; 4amino-2-hydroxybutylyldibekacin

AMINOSID BAN TONG HP

Netilmicin

Netilmicin = ethyl-sisomicin, Nhom ethyl v tr 1 # vi aminohydroxybutyric amikacin. Pho khang khuan tng ong vi pho cua amikacin oc tnh yeu hn amikacin nhat la oc tnh tai.

Neomycin
H C NH2 4' 2 HO HO
3' 2' 1' 6'

I
Neamin
H2N 3 6 OH 1 2 NH2

NH2 O O
4

5 HO CH2

Neomycin B R1 = H, R2 = CH2NH2 Neomycin C R1 = CH2NH2, R2 = H

HO

4"

R1
R2 3" 2"

O
1"

II Neobiosamin
OH

HO

OH Neosamin

Neomycin trch t Streptomyces fradiae. Hoat pho cua neomycin gan giong streptomycin nhng nhay cam hn vi salmonella. Chat nay rat oc oi vi than, ch dung ngoai

Dexamethasone and Neomycin Ear Spray Hydrocortisone and Neomycin Cream Hydrocortisone Acetate and Neomycin Ear Drops Hydrocortisone Acetate and Neomycin Eye Drops Neomycin Eye Drops Hydrocortisone Acetate and Neomycin Eye Ointment Neomycin Eye Ointment

Neomycin Oral Solution

Neomycin Tablets

Spectinomycin

OH H3C - NH H O H O CH3

HO

O H OH O NH -CH3

Spectinomycin ly trch t spectabilis

Cau truc n gian (N,N-dimethyl streptamin ket hp vi mot dan chat cua ose khac bi mot lien ket hemicetal va mot cau ether).

Dung tr lau cau (e khang penicillin)

Fortimicin A

Diamino-1,4 cyclitol, co c t M. olivoasterospora. ng diamino khong cha nhom OH. Fortimicin A (Astromicin), co pho tng ong vi amikacin Nhieu dan chat con ang nghien cu, dactimicin: t oc va hieu qua tren mam e khang

Astromicin

H3 C HO O H 3C H 3C N O NH2 O O OH

CH3

NH 2

NH CH NH Dactimicin
Astromicin

KET LUAN

Aminosid la nhng khang sinh qu: hoat tnh manh, pho rong nhat la oi vi vi khuan gram am, Tuy vay, con nhieu oc tnh va de b e khang. S xuat hien cua cephalosporin III, monobactam, quinolon de s dung va co hoat tnh tren Pseudomonas a han che s phat trien cua aminosid. Ngc lai, s ket hp vi cac chat c che enzym transferase co the la mot hng mi cua nhom nay.