beta lactamase inhibitors of b.pharm 6th sem

pharmacy notes

1. Branch –PHARMACY
Medicinal Chemistry III (BP 601T)
DR. APJ ABDUL KALAM TECHNICAL UNIVERSITY
By
Dr. Rakhi Mishra
Associate Professor
NIET (Pharmacy Institute)
Greater Noida
Lecture –4
Beta Lactam Antibiotics-(Part-4)

2. β-lactamase Inhibitors
•β-lactamasesareafamilyofenzymesproducedby
manygram-positiveandgramnegativebacteriathat
inactivateβ-lactamantibioticsbyopeningtheβ-lactam
ring.
•Hasnegligibleantibacterialactivityorveryweak
antibacterialaction.
•Importantincombinationwithpenicillinssensitiveto
β-lactamasedegradation.
•GivenwithPenicillinswhichincreasesspectrumof
activity.
•Microbialresistancetobetalactamantibiotics.

3. β-lactamase Inhibitors
•Examplesofβ-lactamaseinhibitorsare:-
Clavulanicacid
Sulbactam
Tazobactam

4. β-lactamase Inhibitors
CLAVULANICACID
•Clavulanicacidisthefirstoneofthisclass.
•Itisnaturalproductfromstreptomyces.
•Hasarapidoralabsorption
•Additionofclavulanicacidre-establishestheactivityof
amoxicillin
•IndicatedforRespiratorytract,Skin&Softtissue,
intraabdominalinfections.
•Dosage:100mg/kg/dayin4divideddoses

5. β-lactamase Inhibitors
SULBACTAM
•2–3timeslesspotentthanclavulanicacid
•Oralabsorptionofsulbactamisinconsistent,
thereforepreferablygivenparentrally.
•Ithasbeencombinedwithampicillinforuseagainst
theβ-lactamase
•Usedcommonlyinsurgicalinfectionsandgonorrhea.
•Dosage:- AmpicillinwithSulbactum:
200mg/kg/dayin4divideddoses.

6. β-lactamase Inhibitors
TAZOBACTUM
•Itissimilartosulbactam.
•Itspharmacokineticsmatcheswithpiperacillinwith
whichithasbeencombinedforuseinsevereinfections
likeperitonitis,pelvic/urinary/respiratoryinfections
causedbyβ-lactamaseproducingbacilli.
•Dosage:-Piperacillin+Tazobactum:200-300mg/kg/day
in3divideddoses

7. β-lactamase Inhibitors
MECHANISM OFACTION
•β-lactamasesareafamilyofenzymesproducedby
manygram-positiveandgram-negativebacteriathat
inactivateβ-lactamantibioticsbyopeningtheβ-lactam
ring.
•β-lactamases(β-lactamases,alsoknownas
Penicillinase)thatprovidemultiresistancetoβ-lactam
antibiotics.
•Betalactaminhibitorsbindstoβ-lactamaseenzymeand
inactivatethem

8. β-lactamase Inhibitors
β-lactam Antibiotic β-lactam Antibiotic + β-lactamase inhibitors
Contains β-lactam ring Complex
Inactive compounds Effectiveness of β-lactamase is diminished
Enhances the activity of β-lactam antibiotic

9. β-lactamase Inhibitors

10. β-lactamase Inhibitors
STRUCTUREACTIVITYRELATIONSHIP
•β-LactamRingisessential
•SulphurofpenicillinisreplacedbyO
•NosubstitutionatC-6isrequiredfrotheactivity
•Carboxylicacidisessentialfortheactivity.
•RstereochemistryisgoodatC-3

11. β-lactamase Inhibitors
USES
•Skinandsofttissueinfection,intraabdominal
gynaecologicalsepsis,urinary,biliaryand
respiratorytractinfection
•Gonorrhoea:- 3gamoxicillin+o.5gclavulanic
acid+1gprobenecid-highlycurative.
Adverseeffects:
•G.I.toleranceispoor.
•Candidastomatitis/vaginitis&rashes.

12. MONOBACTAMS
•Monobactamsareβ-lactamcompoundswhereintheβ-
lactamringisaloneandnotfusedtoanotherring,in
contrasttomostotherβ-lactams.
•TheyareeffectiveonlyagainstaerobicGram-negative
bacteria.•(e.g.,Neisseria,Pseudomonas).
•Otherexamplesofmonobactamsare•aztreonam.
tigemonam,nocardicinA,•andtabtoxin.
•Aztreonam.(Thefour-memberedringatthebottomis
theβ-lactam.Thereisasecondthiazolering,butitisnot
fusedtotheβ-lactamring.)

13. MONOBACTAMS
AZTREONAM
•Thisdrugismonocyclicβ-lactam(monobactam)
•Thefour-memberedringatthebottomistheβ-lactam.
•Thereisasecondthiazolering,butitisnotfusedto
theβ-lactamring.

14. MONOBACTAMS
•Aztreonamhavehighlypolarstructurewhichreduces
theoralbioavailability
•Itisrecommendedtogiveparenterally
•Theantimicrobialspectrumofaztreonamisdifferent
fromotherbetalactams.Ithasresemblanceto
aminoglycosides
•Limitedactivityagainstgrampositivebacteriaand
anaerobicbacteria.

15. MONOBACTAMS
MECHANISM OFACTION
•Monobactamsinhibitthebacterialgrowthby
interferingwiththetranspeptidasecatalyzereactionof
bacterialcellwallsynthesis
•Covalentlybindstopenicillinbindingprotein(PBP)to
preventthegrowthofcell.

16. MONOBACTAMS
STRUCTUREACTIVITYRELATIONSHIP
•Carboxylgroupincreasesthe
activityagainstPseudomonas
•Aminothiazolegroupimparts
actionagainstgramnegative
bacterias
•4alphamethylgroupdecreasesits
degradationbybeta-lactamaseenzyme.
•Sulphonylmoeityincreasestheactivityofbetalactam
ring

17. THANK YOU