Fosfomycin is an antibiotic discovered in soil in 1966. It acts by inhibiting the first step of bacterial cell wall biosynthesis through covalent inactivation of the MurA enzyme. This occurs via nucleophilic opening of fosfomycin's epoxide ring. Fosfomycin shows activity against a wide range of gram-positive and gram-negative bacteria including E. coli. Resistance is rare but it is usually combined with other antibiotic classes like beta-lactams or aminoglycosides. It is indicated for severe hospital-acquired infections and those caused by multidrug-resistant organisms.

1. FOSFOMYCIN
(Spain – 1966)
 Khaùng sinh phosphonic
 1969 ly trích töø moâi tröôøng nuoâi caáy Streptomyces fradax.
 Ngaøy nay fosfomycin laø moät khaùng sinh toång hôïp
 Khoâng toàn taïi baát kyø söï ñeà khaùng cheùo naøo vaø noù coù theå
söû duïng baèng caùch keát hôïp vôùi nhieàu khaùng sinh khaùc
(betalactam, aminosid, glycopeptid).
P
OH
OHO
CC
OH3C
H H(S) (R)

2.  Fosfomycin = Acid L (-)
cis epoxy 1,2 propyl
phosphonic
 Caáu truùc epoxy raát hoaït
ñoäng
1 lieân keát carbon –
phosphor (acid phosphonic)
2C baát ñoái : C1 (R) vaø C2
caáu (S).
Caáu truùc
P
OH
OHO
CC
OH3C
H H(S) (R)

3. PCl3 + 2 Me3C-OH
Et3N
C6H6
Cl-P (O-tBu)2
CH C-CH2OH
P
O
O OtBu tBu
H2CCCH
45 o
C, 2h
CH2 C CH P O
O
O tBu
tBu
H2+Pd/C C C
H H
Me P
O
OH
OH
TỔNG HỢP TÒAN PHẦN FOSFOMYCIN
(+) alpha-phenethylamin
EtN3/H2O/Na2WO4
1h 50-55 o
C
C C
H H
Me P
O
O
O
(S) (R)
2C6H5-CH
CH3
NH3
C C
H H
Me P
O
O
O
O
+
(R) (S)
O
H
(-) fosfomycin
?

4. Fosfomycin sodium
Fosfomycin trometamol
2-Amino-2-(hydroxymethyl)propane-1,3-diol hydrogen
(2R,3S)-(3-methyloxiran-2-yl)phosphonate
Fosfomycin calcium
A white or almost white, very
hygroscopic powder, very soluble in
water, sparingly soluble in methanol,
practically insoluble in ethanol and in
methylene chloride.
Very soluble in water, slightly soluble in ethanol (96 per
cent) and in methanol, practically insoluble in acetone.
A white or almost white powder,
slightly soluble in water, practically
insoluble in acetone, in methanol and
in methylene chloride.
[gói bột uống , trị nhiễm trùng tiểu (E coli) liều duy nhất]
(Viên nang, hỗn
dịch uống)(Bột pha tiêm)

5. Kieåm nghieäm
Ñònh tính
- Phoå IR
- Định tính các cation đi kèm
- Phaûn öùng xaùc ñònh nhoùm epoxy
- Phaûn öùng xaùc ñònh nhoùm phosphonic
KTK
- Naêng suaát quay cöïc
- Taïp chaát lieân quan
(1,2-dihydroxypropyl)phosphonic acid,Ñònh löôïng
- PP chuaån ñoä oxyhoùa – khöû
- PP HPLC
- PP vi sinh vaät

6. √ P=O

7. IDENTIFICATION
First identification A, D.
Second identification B, C, D.
B. Dissolve about 0.1 g in 3 ml of a 25 per cent V/V
solution of perchloric acid R. Add 1 ml of 0.1 M
sodium periodate and heat on a water-bath for 30
min. Allow to cool and add 50 ml of water R. Neutralise
with a saturated solution of sodium hydrogen carbonate
R and add 1 ml of a freshly prepared 400 g/l solution of
potassium iodide R. Prepare a blank at the same time
and in the same manner. The test solution remains
colourless and the blank is orange.
Fosfomycin Sodium

8. CÔ CHEÁ KHAÙNG KHUAÅN
Fosfomycin diệt khuẩn bằng cách ức chế giai đọan
đầu tổng hợp peptidoglycan.
Fosfomycin covalently inactivates the first enzyme in the bacterial cell wall
biosynthesis pathway, UDP-N-acetylglucosamine enolpyruvyl transferase
(MurA) by alkylation of the cysteine-115 residue. The inactivation reaction
occurs through nucleophilic opening of the epoxide ring.

9. Fosfomycin covalently inactivates the first enzyme in the
bacterial cell wall biosynthesis pathway, UDP-N-acetylglucosamine
enolpyruvyl transferase (MurA) by alkylation of
the cysteine-115 residue
The inactivation reaction occurs
through nucleophilic opening of the epoxide ring
Resistance to fosfomycin can occur through chromosomal mutations
that result in reduced uptake or reduced MurA affinity for the
inhibitor.
Plasmid-mediated resistance mechanisms involve
conjugative bioinactivation of the antibiotic with glutathione.
The frequency of resistant mutants in in vitro studies has
been low, and there appears to be little cross-resistance
between
fosfomycin and other antibacterials.

10. PHOÅ KHAÙNG KHUAÅN
 Phoå khaùng khuaån khaù roäng goàm tuï caàu, pheá caàu, Haemophilus,
E coli, Klebsiella, Salmonella, Enterobacter, Serratia, Proteus
mirabilis.
 Duøng ñôn trò xaûy ra raát sôùm hieän töôïng choïn loïc caùc chuûng vi
khuaån ñeà khaùng. Söû duïng baét buoäc phaûi phoái hôïp vôùi moät
khaùng sinh khaùc (β-lactam, aminoside, glycopeptid)

11.  CHÆ ÑÒNH
 Fosfomycin ñöôïc chæ ñònh chuû yeáu trong caùc tröôøng hôïp
nhieãm truøng naëng taïi beänh vieän
 Luoân luoân keát hôïp vôùi moät trong nhöõng loaïi khaùng sinh sau
ñaây: beta lactamin, aminosid, glycopeptid
 Ñöôïc chæ ñònh trong tröôøng hôïp vieâm maøng naõo muû, nhieãm
truøng phoåi naëng, nhieãm truøng tieåu naëng, vieâm noäi taâm maïc
nhieãm truøng, nhieãm truøng maùu, nhieãm truøng xöông khôùp…