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Khng sinh: Cng ngh v ng dng CHNG I: TNG QUAN V KHNG SINH 1.1. Gii thiu lch s cht khng sinh: S pht trin v vi sinh vt hc ni chung, v vi sinh vt cng nghip ni ring, vi bc ngoc lch s l pht minh v i v cht khng sinh ca Alexander Fleming (1982) m ra k nguyn mi trong y hc: khai sinh ra ngnh cng ngh sn xut cht khng sinh v ng dng thuc khng sinh vo iu tr cho con ngi. Thut ng" cht khng sinh" ln u tin c Pasteur v Joubert (1877) s dng m t hin tng km hm kh nng gy bnh ca vi khun Bacillus anthracis trn ng vt nhim bnh nu tim vo cc ng vt ny mt s loi vi khun hiu kh lnh tnh khc. Babes (1885) nu ra nh ngha hot tnh khng khun ca mt chng l c tnh tng hp c cc hp cht ho hc c hot tnh km hm cc chng i khng. Nicolle (1907) l ngi u tin pht hin ra hot tnh khng khun ca Bacillus subtilis c lin quan n qu trnh hnh thnh bo t ca loi trc khun ny. Gratia v ng nghip (1925) tch c t nm mc mt ch phm c th s dng iu tr hiu qu cc bnh truyn nhim trn da do cu khun. Mc d vy, trong thc t mi ti nm 1929 thut ng " Cht khng sinh" mi c Alexander Fleming m t mt cch y v chnh thc trong bo co chi tit v penicillin. Thp k 40 v 50 ca th k XX ghi nhn nhng bc tin vt bc ca ngnh cng ngh sn xut khng sinh non tr, vi hng lot s kin nh : Khm ph ra hng lot Cht khng sinh, th d nh Griseofulvin (1939), Gramicidin S (1942) , Streptomycin (1943), Bacitracin (1945), Chloramphenicol v Polymyxin (1947), Chlotetracycline v Cephalosporin (1948), Neomycin (1949), Oxytetracycline v Nystatin (1950), Erythromycin (1952), Cycloserin (1954), Amphotericin B v Vancomycin (1956), Metronidazol, Kanamycin v Rifamycin (1957)... p dng phi hp cc k thut tuyn chn v to ging tin tin (c bit l cc k thut gy t bin, k thut dung hp t bo, k thut ti t hp gen...) to ra nhng bin chng cng nghip c nng lc "siu tng hp" cc cht khng sinh cao gp hng ngn vn ln cc chng ban u. Trin khai thnh cng cng ngh ln men chm quy m sn xut cng nghip sn xut Penicillin G (1942) v vic hon thin cng ngh ln men ny trn cc sn phm khc. Vic pht hin, tinh ch v s dng axit 6-aminopenicillanic (6-APA, 1959) lm nguyn liu sn xut cc cht khng sinh penicilin bn tng hp cho php to ra hng lot dn xut penicilin v mt s khng sinh -lactam bn tng hp khc. nh ngha khng sinh: Cht khng sinh c hiu l cc cht ho hc xc nh, khng c bn cht enzyme, c ngun gc sinh hc (trong ph bin nht l t vi sinh vt), vi c tnh l ngay nng thp (hoc rt thp) c kh nng c ch mnh m hoc tiu dit c cc vi sinh vt gy bnh m vn m bo an ton cho ngi hay ng vt c iu tr. 1.2. n v khng sinh: Nng lc tch t khng sinh ca chng hay nng cht khng sinh thng c biu th bng mt trong cc n v l: mg/ml, g/ml, hay n v khng sinh UI/ml (hay UI/g, International Unit). n v ca mi khng sinh c nh ngha l lng khng sinh ti thiu pha trong mt th tch quy c dung dch c kh nng c ch hon ton s pht trin ca chng vi sinh vt kim nh chn, th d, vi penicillin l s miligam penicillin pha vo trong 50 ml mi trng canh thang v s dng Staphylococcus aureus 209P lm chng kim nh; vi Streptomicin l s miligam pha trong 1 ml mi trng canh thang v kim nh bng vi khun Escherichia coli. 1.3. 1

Khng sinh: Cng ngh v ng dng Hot tnh khng sinh c hiu: Hot tnh khng sinh c hiu l c tnh cho thy nng lc km hm hay tiu dit mt cch chn lc cc chng vi sinh gy bnh, trong khi khng gy ra cc hiu ng ph qu ngng cho php trn ngi bnh c iu tr. c tnh ny c biu th qua hai gi tr l: Nng km hm ti thiu (Minimun Inhibitory Concentration - vit tt l MIC) v nng dit khun ti thiu (Minimun Bactericidal Concentration - vit tt l MBC), xc nh trn cc i tng vi sinh vt gy bnh kim nh la chn tng ng cho mi cht khng sinh. 1.4. 1.5. Ph khng khun ca khng sinh: Ph khng khun ca cht khng sinh biu th s lng cc chng gy bnh b tiu dit bi khng sinh ny. Theo , cht khng sinh c th tiu dit c nhiu loi mm bnh khc nhau c gi l cht khng sinh ph rng, cht khng sinh ch tiu dit c t mm bnh l cht khng sinh ph hp. C ch tc dng: C ch tc dng ln vi sinh vt gy bnh (hay cc i tng gy bnh khc - gi tt l mm bnh) ca mi cht khng sinh thng mang c im ring, ty thuc vo bn cht ca khng sinh , trong , nhng kiu tc ng thng gp l: - Lm ri lon cu trc thnh t bo hay c ch s thnh lp vch t bo. - Ri lon chc nng iu tit qu trnh vn chuyn vt cht ca mng t bo cht hay c ch nhim v ca mng t bo. - Lm ri lon hay c ch qu trnh sinh tng hp protein. - Ri lon hay c ch qu trnh tng hp Acid Nucleic, hoc tng tc c hiu vi nhng giai on nht nh trong cc chuyn ha trao i cht (hnh 1.1). 1.6.

Hnh 1.1. V tr tc dng chnh ca mt s cht khng sinh [1] 2

Khng sinh: Cng ngh v ng dng 1.6.1. c ch s thnh lp vch t bo: Gm cc khng sinh nh: Bacitracin, Cephalosprorins, Cycloserine, Penicillins, Ristocetin, Vancomycin. Khc vi ngi v ng vt, t bo vi khun c vch. Vch t bo vi khun chim 20% trng lng kh ca vi khun. Nh c vch m vi khun gi c hnh dng v bo v t bo trc tc ng ca p sut. p sut ca t bo vi khun Gram dng ln hn Gram m t 3 n 5 ln. Khi s tng hp vch t bo b c ch do tc dng ca khng sinh, cc vi khun Gram dng bin thnh dng hnh cu khng c vch (protoplast), v cc vi khun Gram m c vch khng hon chnh (spheroplast). Nhng hnh thc ny lm t bo d b v mi trng c trng lc bnh thng. Vch t bo vi khun l phc hp polyme c g l Mucopeptide, Mureine, Peptidoglycan gm polysaccharide v mt chui polypeptide c ng ni cho. Polysaccharide l ng c amine, N acetylglycosamine v acetyl muramic acid ch c t bo vi khun. Nhng ng ni cho bt ni vi chui peptide (v d cu ni pentaglycine). cho p ng chuyn vn peptide nh xc tc vi mt s enzyme. Peptidoglycan vi khun Gram dng nhiu hn vi khun Gram m. Tt c cc loi thuc Penicillins v Cephalosporins u l nhng cht c ch s tng hp vch t bo ca vi khun. Giai on u tin: thuc gn vo receptor ca t bo gi l PBP Penicillins gn kt proteine (PBP) t s 3 6 (phn t lng t 40.000 120.000), receptor ny c nhiu t bo vi khun. Receptor PBP c i tnh khc nhau i vi mi loi thuc v kiu tc ng ca n cng khc nhau. V d khi penicillin gn vo receptor PBP, p ng ch yu l ko di t bo mt cch khng bnh thng cng vi nhng tc ng ph thm khc a n t bo vi khun b tan v. Receptor PBP t di s kim st ca nhim sc th, s t bin c th lm thay i s lng receptor v i tnh ca n i vi thuc thuc nhm -lactamins. Sau khi gn vo mt hay nhiu th th thuc s phong b transpeptidase, lm ngn chn vic tng hp peptidoglycan, mt thnh phn quan trng ca vch t bo. C ch ca vic phong b transpeptidase c l do enzyme ny gn vo penicillins hoc cephalosporins c cu trc tng t vi acyl-D-alanyl-D-alanyl, mt phn t m enzyme bnh thng vn tc ng, nn tc ng ca enzyme b phong b. Giai on tip theo c lin quan n vic hot ho cc enzyme t tiu (autolytic enzymes) gy ra s ly gii ca t bo mi trng ng trng (isotonic). Trong mi trng u trng, nhng t bo b bin i thnh protoplast hay spheroplast ch c bao bc bi mt mng t bo mng manh nn rt d v. nhng t bo vi khun ny s tng hp protein v nucleic acid c th cn tip tc mt thi gian. c tnh ca cc thuc khng sinh trong nhm -lactamins i vi t bo ng vt c v s cng ging nh c tnh trn vi khun trong trng hp khng cn vch v peptidoglycan. Penicillins v Cephalosporins ch ng khc nhau i vi vi khun Gram dng v Gram m tu vo s khc bit ca cu trc vch t bo, tng s peptidoglycan, s receptor, l, (pore), lng lipide, ng ni cho t nhin v hot tnh ca enzyme t tiu... chnh n nh tnh xuyn thm, gn kt v hot tnh ca thuc. Tc ng ch ng vi khun ca khng sinh trong nhm -lactamins tu thuc vo s khc bit v cu trc v c tnh v chc nng ca mng. i vi vi khun Gram m do c mng phospholipide bn ngoi nn tr ngi cho thuc bng qua. Nhng thuc c phn t a nc hydrophilic (nh Ampicilline, Amoxicilline), nhng thuc c phn t qua c l (pore) mng bng qua mng t bo vi khun Gram m nhanh hn penicilline G. i vi vi khun Gram dng th mng phospholipide rt khim khuyt v chc nng nh hng ro ngn chn li khng c.

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Khng sinh: Cng ngh v ng dng Amdinocillin l dn xut ca acid amidinopenicillanic ch gn kt vo receptor PBP-2 tc ng rt mnh trn t bo vi khun Gram m hn Gram dng. Amdinocillin c tc ng hip ng vi nhng thuc khc nhau trong nhm -lactamins trn receptor PBP. iu quan trng m lm sng rt quan tm l vi khun khng cn b thuc trong nhm -lactamins ch ng na l do vi khun sn xut c -lactamase, enzyme ny ph v vng -lactam lm tiu tan hiu ng sinh hc ca thuc. l s khng thuc mang tnh di truyn do plasmid kim sot. V d nh s khng thuc do plasmid ca Staphylococcus v mt s vi khun Gram m ng rut. cho penicillin b enzyme ny thu phn ph v vng -lactam ngi ta cho phi hp vi clavulanic acid hoc sulbactam, hoc phi hp amoxicillin vi clavulanic acid dng trong nhng trng hp vim nhim Heamophilus sn xut c enzyme -lactamase. C mt s khng sinh khng li enzyme -lactamase l do vng -lactam c cng c bng gc methoxy, hoc nhm chc khc v d nh methicilline, cefoxitine khng d b enzyme ny ph v. Mt s thuc khng sinh khc nh Bacitracin, Vancomycin, Ristocetin v Novobiocin ch c ch giai on u ca vic tng hp peptidoglycan. Do vic tng hp giai on u ny xy ra bn trong mng t bo cht, nn thuc phi c ngm vo bn trong mng mi c tc dng. Cycloserine, mt cht tng ng vi D-alanine trong chui pentapeptide cho nn thuc cng can thip vo s tng hp peptidoglycan. Cycloserine phong b tc ng ca enzyme alanineracemase - mt loi enzyme kt ni D-alanine vo chui pentapeptide ca petidoglycan. Cycloserine cng c ch enzyme giai on u trong tin trnh tng hp peptidoglycan. 1.6.2. c ch nhim v ca mng t bo: Gm Amphotericin B, Colistin, Imidazoles, Polymyxins. T bo cht ca tt c t bo sng c bao bc bi mng t bo cht, l hng ro c tnh thm chn lc rt quan trng m nhim chc nng bt cu cho vn chuyn ch ng qua mng. Nu chc nng ca mng t bo cht b tn hi th nhng phn t ln v ion b thot ra ngoi, t bo s b hy hoi. Mng t bo cht ca t bo vi khun d b hu hoi hn t bo ng vt, nh vy dng ho hc tr liu mng t bo cht ca t bo vi khun s b ph hu m t bo ng vt vn c che ch. i din cho c ch ny l cc polymyxins tc ng ln vi khun Gram m v cc polyenes tc ng ln vi nm. Polymyxins khng tc ng ln vi nm v ngc li polyenes khng tc ng ln vi khun. iu ny l do mng t bo vi nm cha sterols cn mng t bo vi khun th khng. Polyenes phi tng tc vi mt sterol trong mng t bo vi nm mi c hiu qu tc dng, trong khi mng t bo vi khun th khng c sterol nn polyenes khng tc dng. Tri li, polymyxins khng c tc ng ln t bo vi nm c sterol. Cc thuc khng nm nhm imidazoles (miconazol, clotrimazol, ketoconazol) lm tn hi n tnh nguyn vn ca mng t bo nm do c ch sinh tng hp lipid ca mng. 1.6.3. c