Structure ofPenicillinsOCH3HI1CH3RCNthiazolidineβ-lactamringringpharmacologicalcharacteristicsNCOOHamidaseThe nature of the R group determines the drug's resistance to enzymatiooracidichydrolysisinthe gastrointestinal tract,and affects itsantibacterial spectrum0=CH3HcysteineCH3CHCNatural penicillinsareacombi-nationofaminoCOOHNpenicillinGacidsvaline
Structure of Penicillins The nature of the R group determines the drug’s resistance to enzymatic or acidic hydrolysis in the gastrointestinal tract, and affects its antibacterial spectrum Natural penicillins are a combi-nation of amino acids
SubstitutentsAmidase*Beta-Lactam RingBPenicillinase*Penicillin
ThemainmechanismofResistanceresistance istheproduction by thebacteriumofpenicillinases,O=CH3orβ-lactamasesHCH3R-CNEscherichia coli andHaemophilus influenzaeCOOHare frequently resistantβ-LactamaseClavulanic acid(andCsulbactam andtazobactam)inhibit thoseenzymes,and maybeCH-CH,OHusedtocounterresistance:ClavulanicacidCOOHOther mechanisms are reduced permeability of outer membranes,andmodifications ofbindingsites
Resistance The main mechanism of resistance is the production by the bacterium of penicillinases, or b-lactamases Escherichia coli and Haemophilus influenzae are frequently resistant Clavulanic acid (and sulbactam and tazobactam) inhibit those enzymes, and may be used to counter resistance: Other mechanisms are reduced permeability of outer membranes, and modifications of binding sites
A Case of Resistance: MRSAImpetigo caused by Methicillin甲氧西林-ResistantStaphylococcus金黄色葡萄球菌（MRSA）aureusStaphylococcusaureusisnaturallypresentontheskinandmucosa.Itoftencauses infectionsin elderlyorhospitalized people.Penicillin-resistant strainsof Staphylococcusaureus becameamajorthreat inhospitals and nurseries in the 1950s. Resistance to Methicillin 甲氧西林 emerged in the 1980s. Vancomycin 万古霉素 is then the onlyremaining drug,but in 1996,afirst caseof resistancetovancomycinwas reportedfromJapan.Isolation ofpatient and dedicated carearetheonlyoptionsleft
A Case of Resistance: MRSA Impetigo caused by Methicillin甲 氧西林-Resistant Staphylococcus aureus 金黄色葡萄球菌 (MRSA) Staphylococcus aureus is naturally present on the skin and mucosa. It often causes infections in elderly or hospitalized people. Penicillinresistant strains of Staphylococcus aureus became a major threat in hospitals and nurseries in the 1950s. Resistance to Methicillin 甲氧西 林 emerged in the 1980s. Vancomycin 万古霉素 is then the only remaining drug, but in 1996, a first case of resistance to vancomycin was reported from Japan. Isolation of patient and dedicated care are the only options left
O=CH3HVarious PenicillinsRCH3-CNVariations on radical R:COOHNoralresistancetoAfewmajorpenicillinsnaturalpenicillinaseabsorptionpenicillinsPenicillinGHnopoorPenicillin Gmore active(benzylpenicillin)againstNeisseria,butO—CH,-PenicillinVgoodnopenicillinvmore resistant(phenoxymethylp.)CIto acid+methicillinDicloxacillingoodyesNand1CH3CIflucloxacillinCH -Ampicillingoodnomore activeon Gram(-)NH2bacilli,thereforeCHAmoxicillinexcellentHOnocalledextended-NH21spectrumpenicillins
Various Penicillins Variations on radical R: more active on Gram( -) bacilli, therefore called “ extended - spectrum ” penicillins +methicillin and flucloxacillin natural penicillins Penicillin G more active against Neisseria, but penicillin V more resistant to acid aminopenicillins