Fleming and PenicillinFleming and Penicillin

ChemotherapyChemotherapy

The use of drugs to treat a diseaseThe use of drugs to treat a disease

Selective toxicitySelective toxicity: A drug that kills : A drug that kills harmful microbes without damaging the harmful microbes without damaging the hosthost

Antibiotic/AntimicrobialAntibiotic/Antimicrobial

AntibioticAntibiotic: Chemical : Chemical produced by produced by a microorganisma microorganism that kills or that kills or inhibits the growth of another inhibits the growth of another microorganismmicroorganism

Antimicrobial agentAntimicrobial agent: Chemical : Chemical that kills or inhibits the growth of that kills or inhibits the growth of microorganismsmicroorganisms

Microbial Microbial Sources of Sources of AntibioticsAntibiotics

Antibiotic Antibiotic Spectrum of ActivitySpectrum of Activity

No antibiotic is effective against all No antibiotic is effective against all microbesmicrobes

Mechanisms of Antimicrobial Mechanisms of Antimicrobial ActionAction

Bacteria have their own enzymes for:Bacteria have their own enzymes for: Cell wall formationCell wall formation Protein synthesisProtein synthesis DNA replicationDNA replication RNA synthesisRNA synthesis Synthesis of essential metabolitesSynthesis of essential metabolites

Mechanisms of Antimicrobial Mechanisms of Antimicrobial ActionAction

Viruses use host enzymes inside host Viruses use host enzymes inside host cellscells

Fungi and protozoa have own Fungi and protozoa have own eukaryotic enzymeseukaryotic enzymes

The more similar the pathogen and The more similar the pathogen and host enzymes, the more host enzymes, the more side effectsside effects the antimicrobials will havethe antimicrobials will have

Modes of Antimicrobial ActionModes of Antimicrobial Action

Antibacterial AntibioticsAntibacterial Antibiotics Inhibitors of Cell Wall Synthesis Inhibitors of Cell Wall Synthesis

Penicillin (over 50 compounds)Penicillin (over 50 compounds) Share 4-sided ring (Share 4-sided ring ( lactam ring) lactam ring)

Natural penicillinsNatural penicillins• Narrow range of actionNarrow range of action• Susceptible to Susceptible to penicillinase (penicillinase ( lactamase) lactamase)

Prokaryotic Cell WallsProkaryotic Cell Walls

PenicillinsPenicillins

Penicillinase (Penicillinase ( Lactamase) Lactamase)

Figure 20.8

Semisynthetic PenicillinsSemisynthetic Penicillins

Penicilinase-resistant penicillinsPenicilinase-resistant penicillins• Carbapenems: very broad spectrumCarbapenems: very broad spectrum• Monobactam: Gram negativeMonobactam: Gram negative

Extended-spectrum penicillinsExtended-spectrum penicillins Penicillins + Penicillins + -lactamase inhibitors-lactamase inhibitors

Other Inhibitors of Cell Wall Other Inhibitors of Cell Wall SynthesisSynthesis

CephalosporinsCephalosporins 22ndnd, 3, 3rdrd, and 4, and 4thth

generations more generations more effective against effective against gram-negativesgram-negatives

Figure 20.9

Other Inhibitors of Cell Wall Other Inhibitors of Cell Wall SynthesisSynthesis

Polypeptide antibioticsPolypeptide antibiotics BacitracinBacitracin

• Topical applicationTopical application• Against gram-positivesAgainst gram-positives

VancomycinVancomycin• GlycopeptideGlycopeptide• Important "last line" against antibiotic resistant Important "last line" against antibiotic resistant S. S.

aureusaureus

Other Inhibitors of Cell Wall Synthesis

Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporationIsoniazid (INH)Ethambutol

Inhibitors of Protein SynthesisInhibitors of Protein Synthesis Broad spectrum, toxicity problemsBroad spectrum, toxicity problems ExamplesExamples

Chloramphenicol (bone marrow)Chloramphenicol (bone marrow) Aminoglycosides: Streptomycin, Aminoglycosides: Streptomycin,

neomycin, gentamycin (hearing, neomycin, gentamycin (hearing, kidneys)kidneys)

Tetracyclines (Rickettsias & Chlamydia; Tetracyclines (Rickettsias & Chlamydia; GI tract)GI tract)

Macrolides: Erythromycin (gram +, used Macrolides: Erythromycin (gram +, used in children)in children)

Injury to the Plasma MembraneInjury to the Plasma Membrane

Polymyxin B (Gram negatives)Polymyxin B (Gram negatives) TopicalTopical Combined with bacitracin and neomycin (broad Combined with bacitracin and neomycin (broad

spectrum) spectrum)

Inhibitors of Nucleic Acid Inhibitors of Nucleic Acid SynthesisSynthesis

RifamycinRifamycin Inhibits RNA synthesisInhibits RNA synthesis AntituberculosisAntituberculosis

Quinolones and fluoroquinolonesQuinolones and fluoroquinolones CiprofloxacinCiprofloxacin Inhibits DNA gyraseInhibits DNA gyrase Urinary tract infectionsUrinary tract infections

Competitive InhibitorsCompetitive Inhibitors Sulfonamides (Sulfa drugs)Sulfonamides (Sulfa drugs)

• Inhibit folic acid synthesisInhibit folic acid synthesis• Broad spectrumBroad spectrum

Figure 5.7

Antimicrobial ResistanceAntimicrobial Resistance

Relative or complete lack of Relative or complete lack of effect of antimicrobial against a effect of antimicrobial against a previously susceptiblepreviously susceptible microbe microbe

Increase in MICIncrease in MIC

Mechanisms of Antibiotic Mechanisms of Antibiotic ResistanceResistance

• Enzymatic destruction of drugEnzymatic destruction of drug• Prevention of penetration of drugPrevention of penetration of drug• Alteration of drug's target siteAlteration of drug's target site• Rapid ejection of the drugRapid ejection of the drug

Antibiotic Selection for Resistant Antibiotic Selection for Resistant BacteriaBacteria

What Factors Promote What Factors Promote Antimicrobial Resistance?Antimicrobial Resistance?

Exposure to sub-optimal levels Exposure to sub-optimal levels of antimicrobialof antimicrobial

Exposure to microbes carrying Exposure to microbes carrying resistance genesresistance genes

Inappropriate Antimicrobial UseInappropriate Antimicrobial Use

Prescription not taken correctlyPrescription not taken correctlyAntibiotics for viral infectionsAntibiotics for viral infectionsAntibiotics sold without medical Antibiotics sold without medical

supervisionsupervisionSpread of resistant microbes in Spread of resistant microbes in

hospitals due to lack of hygienehospitals due to lack of hygiene

Inappropriate Antimicrobial UseInappropriate Antimicrobial Use

Lack of quality control in manufacture or Lack of quality control in manufacture or outdated antimicrobialoutdated antimicrobial

Inadequate surveillance or defective Inadequate surveillance or defective susceptibility assayssusceptibility assays

Poverty or warPoverty or war Use of antibiotics in foodsUse of antibiotics in foods

Antibiotics in FoodsAntibiotics in Foods Antibiotics are used in animal feeds and Antibiotics are used in animal feeds and

sprayed on plants to prevent infection and sprayed on plants to prevent infection and promote growthpromote growth

Multi drug-resistant Multi drug-resistant Salmonella typhiSalmonella typhi has has been found in 4 states in 18 people who been found in 4 states in 18 people who ate beef fed antibioticsate beef fed antibiotics

Consequences of Antimicrobial Resistance

Infections resistant to available antibiotics

Increased cost of treatment

Multi-Drug Resistant TBMulti-Drug Resistant TB

MRSA MRSA

Methicillin-Resistant Methicillin-Resistant Staphylococcus aureusStaphylococcus aureus

Most frequent nosocomial Most frequent nosocomial (hospital-acquired) pathogen(hospital-acquired) pathogen

Usually resistant to several other Usually resistant to several other antibioticsantibiotics

Vancomycin Resistant EnterococciVancomycin Resistant Enterococci

Proposals to Combat Antimicrobial Proposals to Combat Antimicrobial ResistanceResistance

Speed development of new antibioticsSpeed development of new antibiotics Track resistance data nationwideTrack resistance data nationwide Restrict antimicrobial useRestrict antimicrobial use Direct observed dosing (TB)Direct observed dosing (TB)

Proposals to Combat Antimicrobial Proposals to Combat Antimicrobial ResistanceResistance

Use more narrow spectrum Use more narrow spectrum antibioticsantibiotics

Use antimicrobial associationsUse antimicrobial associations

The Future of The Future of Chemotherapeutic AgentsChemotherapeutic Agents

Antimicrobial peptidesAntimicrobial peptides Broad spectrum antibiotics from plants Broad spectrum antibiotics from plants

and animalsand animals• Squalamine (sharks)Squalamine (sharks)• Protegrin (pigs)Protegrin (pigs)• Magainin (frogs)Magainin (frogs)

The Future of The Future of Chemotherapeutic AgentsChemotherapeutic Agents

Antisense agentsAntisense agents Complementary DNA or peptide nucleic acids Complementary DNA or peptide nucleic acids

that binds to a pathogen's virulence gene(s) and that binds to a pathogen's virulence gene(s) and prevents transcriptionprevents transcription

Antifungal DrugsAntifungal Drugs

Fungi are Fungi are eukaryoteseukaryotes

Have unique Have unique sterols in their sterols in their cell wallscell walls

Pathogenic fungi Pathogenic fungi are often outside are often outside the bodythe body

Antiviral DrugsAntiviral Drugs

Viruses are composed of nucleic acid, Viruses are composed of nucleic acid, protein capsid, and host membrane protein capsid, and host membrane containing virus proteinscontaining virus proteins

Viruses live inside host cells and use Viruses live inside host cells and use many host enzymesmany host enzymes

Some viruses have unique enzymes for Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in DNA/RNA synthesis or protein cutting in virus assemblyvirus assembly

Antiviral DrugsAntiviral DrugsNucleoside and Nucleotide AnalogsNucleoside and Nucleotide Analogs

Figure 20.16a

Figure 20.16b, c

Analogs Block DNA SynthesisAnalogs Block DNA Synthesis

Antiviral DrugsAntiviral DrugsEnzyme InhibitorsEnzyme Inhibitors

Inhibit assemblyInhibit assembly Indinavir (HIV)Indinavir (HIV)

Inhibit attachmentInhibit attachment Zanamivir (Influenza)Zanamivir (Influenza)

Inhibit uncoatingInhibit uncoating Amantadine (Influenza)Amantadine (Influenza)

Antiviral DrugsAntiviral DrugsEnzyme InhibitorsEnzyme Inhibitors

InterferonsInterferons prevent spread of viruses to prevent spread of viruses to new cells (Viral hepatitis)new cells (Viral hepatitis)

Natural products of the immune system in Natural products of the immune system in viral infectionsviral infections

Antiprotozoan DrugsAntiprotozoan Drugs

Protozoa are Protozoa are eukaryotic cellseukaryotic cells

Many drugs are Many drugs are experimental and experimental and their mode of their mode of action is unknownaction is unknown

Antihelminthic DrugsAntihelminthic Drugs

Helminths are Helminths are macroscopic macroscopic multicellular multicellular eukaryotic eukaryotic organisms: organisms: tapeworms, tapeworms, roundworms, roundworms, pinworms, pinworms, hookwormshookworms

Antihelminthic DrugsAntihelminthic Drugs Prevent ATP generation (Tapeworms)Prevent ATP generation (Tapeworms) Alters membrane permeability (Flatworms)Alters membrane permeability (Flatworms) Neuromuscular block (Intestinal Neuromuscular block (Intestinal

roundworms)roundworms) Inhibits nutrient absorption (Intestinal Inhibits nutrient absorption (Intestinal

roundworms)roundworms) Paralyzes worm (Intestinal roundworms)Paralyzes worm (Intestinal roundworms)

Measuring Antimicrobial Measuring Antimicrobial SensitivitySensitivity

E TestE Test MIC: Minimal MIC: Minimal

inhibitory inhibitory concentrationconcentration