TNG HP THUC KHNG SINH KHNG VIRUS HIVCHNG UNG TH

PHN I. THUC KHNG SINHKhng sinh hay hot cht c tnh khng sinh l hp cht to thnh do chuyn ha sinh hc (nm, vi khun sn xut ra) hoc c bn tng hp da trn cc khng sinh t nhin, c kh nng c ch s pht trin hoc s tn ti ca cc vi khun khc nng thp.Cuc chin tranh ha hc ca th gii vi sinh vt c con ngi s dng chng li nhng vi sinh vt gy hi cho ngi v ng, thc vt. Cng lm dng cc loi thuc khng sinh/khng sinh mnh s nhn thuc, quen thuc vi khun thch nghi nhanh hn vi cc loi thuc khng sinh:+) gim s lng nhng loi thuc hu hiu+) nhiu loi vi khun t bin nhn thuc gy ra cc bnh l

Phn loi khng sinh Nhm -LactamNhm AminoglycozitNhm TetracyclineNhm ChloramphenolNhm MacrolidNhm LincosamitNhm PolypeptitaCc nhm khc (rifamycin, chng nm, chng ung th).

Nghin cu pht trin Pht hin hot tnh T mt hp cht mi c tng hp (c cc nghin cu l thuyt v kh nng th hin hot tnh) hoc mt hp cht t nhin c phn lp (t nm, vi khun ) - xc nh tc dng khng sinh.Xc nh mt vi sinh vt gy bnh nht nh mi, chu s tc dng ca loi hot cht/khng sinh no.Nghin cu l thuyt: - Da trn cc phn mm ha hcDa trn cm nhn trc quan ca nh nghin cu: khung cng thc chung ca cc hp cht khng sinh bit. Bin i ha hc t cc hp cht khng sinh/hoc c tnh khng sinh nh (nhm nng cao hot tnh hn).

Nghin cu pht trin Xc nh tc dng khng khun (in vitro)Test pha long: theo di s pht trin ca vi sinh vt trong mi trng c nng gim dn ca khng sinh/hot cht. Xc nh c nng c ch ti thiu (MIC) g/ml v nng dit khun ti thiu (MBC). Nng c ch ti thiu: tc l ti mc nng , vi khun khng pht trin na, tuy nhin khi gp iu kin thun li, vi khun li sinh si. Nng dit khun ti thiu vi khun chu tc ng ca khng sinh cc nng khc nhau, sau chuyn vi khun sang mi trng khng c khng sinh xc nh vi khun c th pht trin ti sinh c hay khng.Lm khng sinh : xc nh ng knh vng v khun, khi so snh vi cc khng sinh khc nng bit, c th xc inh c tc dng khng sinh. Khng sinh - xc nh vng v khun c ch khi tm thuc iu tr thch hp nht cho bnh nhn, sau khi phn lp c chng vi khun nht nh t ngi bnh.Test theo ng vch, xc nh cng lc tc dng ca khng sinh nn nhiu loi vi khun xc nh ph tc dng ca khng sinh mi

Nghin cu pht trin T hp cht bn tng hp:Xc nh tc dng ln chng gy bn v bn ha lT vi sinh vt:Nui cy, chit ly dch cha khng sinh: xc nh tc dng ln chng gy bnh, bn v chit ly tinh th hot cht.

Nghin cu trin khai Khi c kt qu tt giai on nghin cu pht trin, tip tc nghin cu trin khai theo hng:Nghin cu quy trnh v thit b sn xut ln: Ln men v chit xut hoc h thng thit b tng hp ha hc.Thc hin bn tng hp, bin i cu trc t cc hp cht thin nhin/khng sinh nhm tng hp nhng hot cht mi c u im hn hoc hn ch c nhng nhc im khi trin khai lm sng.

Trin khai lm sng Nhc im khi trin khai lm sng: thi gian bn hy, thi tr nhanh, b khng thuc, b thy phn Qua nghin cu pht trin v trin khai thc t, t hng ngn khng sinh nhm penicillin tng hp c, thng mi ha hn 100 hot cht khng sinh c c cc tc dng:Chm thi tr v thi gian bn hy luDng c ng ung (chu dc axit)Khng b phn hy bi enzyme penicillinaseC ph tc dng rng

Cng thc i din ca nhm khng sinh ny c cha vng -lactam.

Vng -lactam thng ngng t vi mt d vng khc. Trn c s to ra hai nhm khng sinh ln l penicillin v cephalosporin.

Penicillin = amid ca A6AP. Mch nhnh RCO c th c to thnh bng cc phn ng bn tng hp hoc c b sung vo trong qu trnh ln men nm mc.

A6AP c th c tng hp t hai axit amin l cystein v valin hoc vi serine. Cu to ca penicillin cho thy tn ti sc cng ln v khng b v mt ha hc. Chnh b khung dipeptit ca penicillin nh la c enzym v cho php penicilline tip xc vi trung tm hot ng ca emzym

C ch tc dngPeptidoglycan l thnh phn c bn to nn vch t bo vi khun, cc penicillin c kh nng axyl ha cc enzym D-analin transpeptidase tham gia qu trnh sinh tng hp peptidoglycan (gy c ch hot)Hot ha enzym murein hydrolase t bo vi khun, phn gii peptidoglycan v vi khun chu tc ng ca lc ngoi bo, gy tn thng, khng pht trin v t cht.

khng sinh c cha vng -lactam 4 cnh

c im v lin quan cu trc hot tnh khng khunS c mt ca vng -lactam.Nhm carboxylic t do, ch cho php cc dn cht tin thuc ti nhm ny vi mc ch h tr dc ng hc ca thuc. i vi h penicillin cn c s c mt ca vng thiazilidin. Sc cng ca h vng -lactam vng ln, tc dng khng khun cng mnh, tuy nhin bn s gim.Mch nhnh axylamino ti v tr 6 l cn thit cho hot tnh. Mch nhanh ny gp phn to nn cc dn xut khc nhau ca h penicillin.Nguyn t S thng gp, tuy nhin c th thay bng C, O. Cu hnh cis ti v tr 5 v 6.

Hn mt na tng s cc khng sinh hin nay l thuc h -lactam. Tuy nhin, chng c hn ch l s tin ha ca cc cc vi sinh vt km theo s xut hin tnh khng i vi tc dng ca khng sinh v v ngy nay t l chng khng thuc tng ln v theo cc c ch sau:Vi khun tit ra enzym -lactamase v hiu ha (thy phn vng -lactam), chuyn thnh cc dn xut khng c hot tnh.Lm thay i cu trc ca mng t bo vi khun; lm bin i hoc ph hy cc enzym transpeptidaza. V d: Nm 1946 c 14% t cu khun khng thuc penicillin; nm 1947 38%; nm 1948 59% v nm 1990 90%.Nhiu trc khun Gr (-) hin ny khng tt c cc loi thuc khng sinh. Acid t nhin clavulanic - khng c hot tnh khng sinh, nhng c s dng trong y hc nh l cht lm n nh penicillin, bi v n c ch tc dng ca enzyme -lactamase, enzyme lm gim hot tnh ca cc penicillin. iu ch ra cc bit dc khng sinh phc hp, v d nh amoxyclab hoc clavulyn [bao gm c amoxycillin v acid clavulanic, trong cc loi thuc ny, acid clavylanoictc ng ln enzyme, cn penicillin khng b cn tr khi tc dng ln cc vi khun gy bnh.

Vi khun sn sinh ra enzyme penicillinaza (-lactamase), enzyme ny d dng ph v vng lactam ca penicillin, chuyn ha n t dn xut ca acid 6-aminopenicillanic (24) thnh dn xut ca acid penicilloinic (25):

Nhm tm ra cc penicillin ung c, khng enzym -lactamaza v c ph khng rng hn so vi penicillin thin nhin, cc nh nghin cu thc hin cc qu trnh:Tng hp sinh hc. Cc penicillin c sinh tng hp t mi trng nui cy Penicillium notatum hoc Penicillium chrysogenum. Hai cht i din nhm c s dng trong iu tr lm sng l penicillin G (benzyl penicellin) v penicillin V (phenoxy metyl penicillin). thu cc penicillin tng ng, ngi ta thm vo mi trng nui cy cc tin cht ph hp. V d, thm axit phenyl acetic iu ch penicillin G hoc axit phenoxyacetic iu ch penicillin V. Tng hp cc khng sinh h penicilline

Bn tng hp.iu ch 6-APA t benzyl penicillin (thu c t phng php sinh hc) bng phng php thy phn khi c mt ca enzim axylaza hoc bng phng php ha hc.Tin hnh axyl ha 6-APA bng cc axit thch hp, nhm thu c cc dn xut ph hp. thc hin tng hp ton phn penicillin nhng do hiu sut thp nn khng c gi tr thc tin cao.

Vi d tng hp Hot cht c tng hp t acidamin, di dng mui vi trietylamine, vi clorua N-methoxymethylenazonicycloheptane

Acid t nhin clavulanic (4) khng c hot tnh khng sinh, nhng c s dng trong y hc nh l cht lm n nh penicillin, bi v n c ch tc dng ca enzyme -lactamase, enzyme lm gim hot tnh ca cc penicillin.

Ph UV. a s cc nhm R (axyl) u l vng thm nn cho ph hp th trong vng UV.

Ph IR. vng 1600-1800 cm-1 c cc pic c trng ca cc nhm lactam (1760-1730 cm-1), nhm chc amid (1700- 1650 cm-1), nhm chc carboxyl ( khong 1600 cm-1).

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