KHNG SINH -LACTAMIN (-LACTAM)

(A)Penam (B)Carbapenam (C)Oxapenam (D)Penem (E)Carbapenem (F)Monobactam (G)Cephem (H)Carbacephem (I)Oxacephem-Lactams skeleton

CC THUC CHNHPenicillin: (PENAM)penicillin G; penicillin Vmethicillin; oxacillinampicillin; amoxicillin; carbenicillin; ticarcillin

Cht c ch -lactamase: (OXAPENAM) acid clavulanic

CARBAPENEM: imipenem

Cephalosporin (CEPHEM)

Th h I :cephalexin; cephalothinTh h II:cefoxitin; cefaclor Th h III:cefotaxime; cefoperazone; ceftriaxone Th h IV:cefepimeTh h V: ceftobiprole

MONOBACTAM:aztreonam

CC THUC CHNH

C CH TC NG CA CC KS H - LACTAM

C CH TC NG CA CC KS H - LACTAM

Vi khun khng - lactamin theo cc c ch sau:

khng enzym: VK sn xut -lactamase

khng khng enzym:- Thay i tnh thm ca mng t bo- Bin mt hoc bin i cc PBP - Do cc efflux pump : bm thuc ra khi t boVd: multidrug resistance (MDR) pumps

C CH KHNG

cephalosporinmonobactamHOT TNH KHNG KHUN Quan h cu trc - tc ng:

Danh php IUPACAmid- 6 ca acid (2S, 5R, 6R-amino-6-dimethyl-3,3-oxo-7-thia-4-aza-1-bicyclo [3.2.0]-heptan carboxylic).

Danh php thng dngPenicillin nh l nhng amid ca acid 6-amino penicillanic (6- APA).

NHM PENICILLIN

Benzyl penicillin = Penicillin G

IU CH

T nm Penicillium notatum.

Penicillin G (thm vo mi trng acid phenylacetic ) Penicillin V (thm vo mi trng acid phenoxyacetic )

60mg/L 20 g/LPhng php sinh hc

Bn tng hp IU CH

Bn tng hp IU CH

Tnh cht vt lCc penicillin di dng mui hoc dng acid l nhng bt trng khng mi khi tinh khit.Ph UVPh IR: vng 1600-1800 cm-11760 v 1730 cm-11700 v 1650 cm-11600 cm-1 - Nng sut quay cc

Tnh acid- To mui natri v kali (bn): tan trong nc, pha timNatri amoxicillin Kali benzylpenicillin Tnh cht ha hc- To mui vi cc amin:Procain penicillin: tc ng ko di 24-48h , Benethamin penicillin: tc ng ko di 3-7 ngy, Benzathin penicillin: tc ng ko di 2-4 tun.

Tnh acid- To thnh nhng este, tin cht ca PNC c kh nng phng thch tr li cc khng sinh ny in vivo.Tnh cht ha hcTin dc ampicillin, gip hp thu KS tt hn qua rut

Tnh khng bn ca vng beta lactam(OH- hay penicillinase)- Chu y tng k vi nhng chat co tnh kiem

S alcol phan va amino phanAcid penicilloicAcid hyroxamic

S m vng -lactam c xc tc bi cc ion kim lai (Phc to thnh vi ion kim lai hat ha s tn cng i nhn) Ch : vng -lactam b m, KS mt tc dng

Tnh khng bn ca vng beta lactam (acid mnh, nng hoc HgCl2)Peni G bn pH= 6-7. Hat tnh KS gim rt nhanh pH

X = NH2, Cl, PhOCONH, heterocyles

Kim nghim NH TNH - Ph IR - Sc k lp mng - Phn ng vi hydroxylamin, sau vi CuSO4 - Phn ng mu vi acid H2SO4 - Phn ng mu vi dd formaldehyd trong H2SO4KIM TINH KHIT - hp thu UV, pH, nng sut quay cc- Cc tp cht thng thng: KL nng- Cc tp cht lin quan: Th d N,N-dimethylanilin (trong ampicillin hoc amoxicillin) bng sc k kh.

NH LNG 1. PHNG PHP OXY HA KH2. PHNG PHP HPLC

3. PHNG PHP VI SINH VT(Xc nh hot lc ca khng sinh: o ng knh vng v khun)Kim nghim

- KS nhm penicillin t c, - Tai bin ch yu do d ng, D ng nh gy nga, ni m ay D ng nng gy shock phn v C TNH V TAI BIN

PENICILLIN NHM IPenicillin thin nhinPenicillin G (benzyl penicillin)Dng tc dng nhanh: Na/K benzyl penicillinDng tc dng chm: procain PNC, benethamin PNC, benzathin PNC

Penicillin V (phenoxy methyl penicillin)Peni GPeni V

T PNC-G: azidocillin, clometocillinPENICILLIN NHM IPenicillin bn tng hp- Bn trong mi trng acid,- Hp thu tt hn, - Hot cht trong huyt thanh cao hn, - T1/2 di hn.T PNC-V: pheneticillin, propicillin, phenbenicillin

Ph khng khun hp, ch yu trn gram (+):Cu khun gram (+): t cu khng tit penicillinase, lin cu, ph cu.Cu khun gram (-): lu cu (khuynh hng tng MIC v xut hin nhng chng khng). Xon khun: Xon khun giang mai, Leptospira v Borelia burgdorferi.Trc khun gram (+): trc khun gy bnh bch hu, bnh than, listeria (vim mng no), erysipelothrix (vim qung).KHNG TC DNG TRN TRC KHUN GRAM (-)PENICILLIN NHM IPh khng khun

PENICILLIN NHM II Meticillin, oxacillin, cloxacillin, dicloxacillin, Ph hp # nhm I, nhng c kh nng khng li penicillinase do S. aureus tit ra- Cloxacillin hp thu rut tt hn oxacillin- Flucloxacillin: t gn vi protein huyt tngCh : S a thay th lm gim hot tnh KS (MIC tng cao hn)Ch : Nhm II ch tt trn S.aureus tit penicillinaseisoxazolyl va cng knh va ht e- bn vi -lactamase v MT acid ung c

XYOxacillin (Bristopen) HHCloxacillin (Orbenin) ClHDicloxacillin (Dicloxil) ClClFluocloxacillin (Floxapen) ClF

-isoxazolyl va cng knh va ht in tUng c- Cc isoxazolyl khc nhau do nhm th halogen trn vng thmThay i v dc ng hc: hp thu, s gn kt vi protein huyt tng:- Cloxacillin hp thu rut tt hn oxacillin-Flucloxacillin: t gn vi protein huyt tng

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2011, p. 20422053 Vol. 55, No. 50066-4804/11/$12.00 doi:10.1128/AAC.01250-10Identification of Pyruvate Kinase in Methicillin-ResistantStaphylococcus aureus as a NovelAntimicrobial Drug TargetUniversity of British Columbia, Vancouver, British Columbia, Canada7Pyruvate kinase (PK), the product of a single-copy gene, was identifiedas a highly connected hub protein in MRSA. Furthermore, wealso found that PK is absolutely essential for S. aureus viabilitybased upon PK antisense and gene disruption experiments(44). The essential requirement for PK for bacterial growthwas also reflected by its high enzymatic activity during theexponential phase of the S. aureus life cycle. Taken together,these findings provide a clear rationale for selecting PK as anovel, candidate drug target

PK (EC 2.71.40) catalyzes the final step in glycolysis with theirreversible conversion of phosphoenolpyruvate (PEP) to pyruvatewith the concomitant phosphorylation of ADP to ATP(38). As PK plays a major role in the regulation of glycolysis, itsinhibition leads to the interruption of carbohydrate metabolismand energy depletion. Moreover, both the substrate andthe product of this reaction feed into a number of biosyntheticpathways, placing PK at a pivotal metabolic intersection

FtsZ is a key bacterial protein involved in microbial cell division (cytokinesis).3,4 It is highly conserved among bacterial pathogens and, inseveral genetic studies, has been shown to be essential for bacterialviability.58 Cell division in bacteria occurs at the site of formationof a cytokinetic Z-ring polymeric structure comprised of FtsZ subunits.9 The vital role that FtsZ plays in bacterial cell division makesthis protein a promising therapeutic target. FtsZ-targeting antibacterialagents can exert their disruptive effects on the Z-ring byeither stabilizing FtsZ polymers or inhibiting their formation.14Bioorganic & Medicinal Chemistry 20 (2012) 701270293-Phenyl substituted 6,7-dimethoxyisoquinoline derivativesas FtsZ-targeting antibacterial agents

Ph KK ca mt penicillin ph thuc vo:- Cu trc Kh nng xuyn mng VK gram mTnh nhy cm vi betalactamse i lc vi enzym mc tiu transpeptidase Tc b bm ra ngai VK gram mM mm (trial and error) tm kim penicillin ph rngMt lng ln cht tng ng c tng hp vi nhng thay i nhnh bn, vi nhng nhn xt SAR nh sau:- Nhm hydrophobic (peni G) tt trn gram + nhng khng tt trn gram _- S gia tng trn gram m tm thy tt nht vi nhng nhm hydrophylic carbon alpha (iu ny c cho l tr gip nhng penicillin ny bng qua porin outer cell membrane ca VK gram m)

1945PENICILLIN NHM III

Th trn C ca chc carboxamid (PNC- G): cc nhm th thn nc amin, hydroxyl, carboxylic, sulfonilicM rng hot ph sang vi khun gram mNghin cu cu trc-tc dng:

III-B: c nhm th trn amin (NH2): Azlocillin, Mezlocillin, PiperacillinPENICILLIN NHM III: gm c 2 phn nhm IIIA v III B: III-A: khng c nhm th trn amin (NH2): Ampicillin, Amoxicillin

PENICILLIN NHM III-A: khng c nhm th trn amin (NH2): Ampicillin, AmoxicillinAmoxicillin - Bn vi acid - Nhng nhy cm vi - lactamase. - Hp thu km qua rut cPh khng khun PNC-G + 1 s VK Gram m:Haemophilus, Escherichia, Proteus mirabilis, Salmonella, Shigella. * Khng tc dng trn nhim trng bnh vin do Enterobacter, Serratia, Proteus indol dng, Providencia, Bacillus pyocyanic

PENICILLIN NHM III-B: c nhm th trn amin (NH2): Azlocillin, Mezlocillin, PiperacillinTc ng trn cc mm khng vi ampicillin (PNCIII-A) nh: Klebsiella, Enterobacter, Serratia, Pseudomonas

Piperacilin phi hp vi aminosid hoc vi cht c ch betalactamase

PENICILLIN NHM IV: (-carboxy-PNC)Carbenicillin, ticarcillin, carindacillinZ=phenyl CarfecillinBn v mt ha hcHot tnh khng khun tng t cc -carboxy-PNC- Hot tnh trn trc khun m xanh- ng vn vi aminosid- Ticarcillin hot tnh 2 ln mnh hn Carbenicillin.

To tin dc di dng ester: indanyl carbenicillin, phenyl carbenicillinAryl ester tt hn alkyl ester v v mt ha hc th aryl ester nhy cm vi s thy gii hn do hiu ng cm ng ht electron (-I) ca vng aryl.Mt ester ko di khng cn thit trong trng hp ny v aryl ester xa vng beta lactam v khng b che (i vi enzym esterase)

PENICILLIN NHM V (6-penicillin)Temocillin (6-methoxy ticarcillin)

Khng sinh ny t hot tnh trn cu khun gram(+) v c hot tnh trung bnh trn vi khun Enterobacterie. - c xem l penicillin khng -lactamase. - Dnh iu tr nhng TH nhim trng VK gram m tit -lactamase (gm nhng chng khng vi cepha III).

PENICILLIN NHM VI (Amidino-PNC)Ph KK hp, tp trung ch yu trn VK gram m.

- Rt nhy cm: Escherichia coli.

- Nhy cm: Yersinia, Salmonella, Shigella,Enterobacter, Citrobacter, Klebsiella (khng sn xut hoc sn xut yu penicillinase).Khng khng cho vi ampicillin(nhn azepin gn trn lin kt amidine)

CHT C CH -LACTAMASEI CNG

Nhiu loi vi khun c kh nng tit ra cc enzym -lactamase phn hy cc khng sinh h beta lactamine. S sn sinh cc enzym ny c th l t nhin hay tip nhn c.Men beta lactamase bao gm penicilinase v cephalosporinase.

More than 200 -lactamases are currently known and grouped into four classes, A, B, C, and D, based on their amino acid sequence and general catalytic properties.

Typically class A -lactamases exhibit a higher activity towards penicillins than towards cephalosporine.

Some of the class A -lactamases are also active against the new generations of cephalosporines and carbapenems.

Cht c ch beta lactamase + cc penicillin: m rng ph khng khun ca nhng cht ny ln cc vi khun tit men penicillinase.

Sau khi gn vi men penicillinase, cc cht ny s b phn hy.C CH TC NGCht c ch -lactamase

Penicillinase

Cht c ch -lactamase

Acid clavuclanic- Thu c t Streptomyces clavuligerus- Cu trc oxapenam- c s dng dng mui kali clavuclanat- Cc phi hp: acid clavuclanic amoxicillin, acid clavuclanic ticarcilinCht c ch -lactamase

Ph khng khun ca phi hp

A. a. clavuclanic amoxicillinCi thin trn nhng mm nhy cm sn xut beta lactamase nh Neiserria gonorhoeae, Haemophilus, E. coli, Salmonella. B. a. clavuclanic ticarcillinPhi hp ny gia tng tc ng trn Staphylococcus (95% Streptococcus nhy cm vi phi hp a.clavuclanic ticarcillin so vi 49% nu ch s dng mt mnh ticarcillin).

Cht c ch -lactamase

Dn cht ca penam, bn tng hp t 6 APACu trc tng t penicillin nhng khng c nhm th C6 (mt C*), S v tr 4 c oxy ha thnh SO2, Cu hnh C2 v C5 ging penicillinSulbactam(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide

Phi hp sulbactam-ampicillinCht c ch -lactamase

- Dn cht este i t sulbactam v ampicillin- Hot tnh trn cu khun gram dng, gram m; trc khun gram dng, gram m- c dng trong tai-mi-hng, h hp, sinh dc, da trn nhng mm nhy cmSultamicillinCht c ch -lactamase

Dn cht ca sulbactam m mt nhm methyl mang nhm th triazolylCht c ch betalactamase khng thun nghch ph rngS dng di dng phi hp tazobactam - piperacillinTazobactam

Cht c ch -lactamase

CARBAPENEM

Thienamycin :

- trch t mi trng nui cy Streptomyces cattleya. - hot tnh khng khun rng - hot tnh trn Pseudomonas - khng li -lactamase Cc k khng bn trong dung dch nc -> dn xut N-formimidoyl

IMIPENEMAcid [hydroxy-1 ethyl (R)]6[[(iminomethylamino-2) ethyl]thio]-3-oxo-7-aza-1bicyclo [3.2.0]hepten-2 carboxylic-2 (5R,6S).

Carbapenem

- Nhn penem v nhm COOH C2 cn thit cho hot tnh khng khun.

- C*6 (S) thay v C*6 (R) penicillin v cephalosporin khng enzym ca VK

- Amino-2-thioethyl (cysteamin) v tr 3 hot tnh trn Pseudomonas.

- N-formimidoyl phn t bn v mt ha hc.

IMIPENEM(S)Carbapenem

IMIPENEMPh khng khun

- Bn vng vi men beta lactamase, ph khng khun rt rng, bao gm:

- Cu khun gram dng: Staphylococcus nhy meticillin (MRSA khng vi imipenem), Strepococcus , Pneumococcus, Enterococcus.

Cu khun gram m: Neisseria

-Trc khun gram dng: Clostridium, Listeria monocytogenes

- Trc khun gram m: H. influenzae, E. coli, Klebsiella, Proteus mirabilis, Enterobacter, Citrobacter, Serratia, Proteus vulgaris, Bacteroides fragilis, Acinetobacter, P. aeruginosae.

Carbapenem

Carbapenem c ph khng khun rng nht trong tt c cc KS lactames.

IMIPENEM - IV chm. - D b phn hy bi dehydropeptidase ng thn khi s dng thng kt hp vi cilastatin (cht c ch enzym dehydropeptidase) gii hn s chuyn ha ny.

Carbapenem

4-Methyl carbapenem

Bn hn i vi s thy gii ca dehydropeptidase

ME1036. ME1036 (CP5609; developed by Meiji Seika, licensedby Forest) is a broad-spectrum carbapenem that bindswith a high affinity to PBP 2a of MRSA (IC50 0.13 to 0.73g/ml) and that exhibits potent in vitro inhibitoryactivity against MRSA . A series of 4-methyl carbapenems having structural similarityto ME1036 showed potent activities against MRSA and PRSP, aswell as against the gram-negative organism ampicillin-resistant,-lactamase-negative Haemophilus influenzae

PZ-601 (Razupenem). PZ-601 (formerly known as SMP-601; licensed from Dainippon Sumitomo Pharma Co., Ltd.,Osaka, Japan) is a new carbapenem currently being developedby Protez Pharmaceuticals (now Novartis) that hasdemonstrated a high degree of potency against MRSA.

British Pharmacopea 2007, 2009,

Imipenem Anoxicillin sodium Amoxicillin trihydrate Cloxacillin sodium

- Cefaclor - Cefadroxil monohydrate- Cefalexin monohydrate- Cefuroxim natri- Cefuroxim acetyl- Ceftriaxone Sodium- Cefotaxime Sodium

MIC = MINIMUM INHIBITORY CONCENTRATION *MRSA Meticillin-resistant S.aureus*Quan h cu trc - tc ng:

- S nguyn vn ca vng beta-lactam- S hin din ca 1 chc tnh acid trn N/C2- S hin din ca nhm acylamin ngoi vng- C* -> cu dng khng gian

*Phng php sinh hc **Acid penicilloic

Acid hyroxamic**Nghin cu cu trc-tc dng: ****MRSA meticillin-resistant S.aureus **