Antimicrobial Drugs

Antimicrobial Drugs Chemicals used to treat microbial infections Before antimicrobials, large number of people died from common illnesses Now many illnesses easily treated with antimicrobials However, many antimicrobial drugs are becoming less useful

Antimicrobial Drugs Chemotherapeutic agent= Antimicrobial drug= Different types of antimicrobial drugs: Antibacterial drugs Antifungal drugs Antiprotozoan drugs Antihelminthic drugs

Paul Ehrlich He observed that certain dyes stain bacterial cells and not animal cells Theorized that there could be a dye or chemical that would harm bacterial cells but not human cells Systematic search for chemical to cure syphilis 606th compound tested proved to be highly effective in treating laboratory animals

Gerhard Domagk Discovered red dye, Prontosil effective in treating Streococcal infections in animals No effect in test tubes Enzymes in animals blood split Prontosil molecule into sulfanilamide- this acted against streptococcal Sulfa Drug

Alexander Fleming Working on cultures of Staphylococcus Contamination with mold Noticed colonies growing near mold looked odd Found that mold was secreting substance that was killing bacteria

Figure 20.1

Features of Antimicrobial Drugs Most modern antibiotics come from species of microorganisms that live in the soil To commercially produce antibiotic: Select strain and grow in broth When maximum antibiotic concentration reached, extract from medium Purify Chemical alter to make it more stable

Features of Antimicrobial Drugs: Selective Toxicity Cause greater harm to microorganisms than to host Chemotherapeutic index= lowest dose toxic to patient divided by dose typically used for therapy

Features of Antimicrobial Drugs: Antimicrobial Action Bacteriostatic: inhibit growth of microorganisms Bactericidal: Kill microorganisms

Features of Antimicrobial Drugs: Spectrum of Activity Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit Some kill only limited range : Narrow-spectrum antimicrobial While others kill wide range of microorganisms: Broad-spectrum antimicrobial

Features of Antimicrobial Drugs: Effects of Combining Drugs Combinations are sometimes used to fight infections Synergistic: action of one drug enhances the activity of another Antagonistic: activity of one drug interferes with the action of another

Features of Antimicrobial Drugs: Adverse Effects Allergic Reactions: some people develop hypersensitivities to antimicrobials Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers

Features of Antimicrobial Drugs: Resistance to Antimicrobials Some microorganisms inherently resistant to effects of a particular drug Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes

Mechanisms of action of Antibacterial Drugs Inhibit cell wall synthesis Inhibit protein synthesis Inhibit nucleic acid synthesis Injury to plasma membrane Inhibit synthesis of essential metabolites

Figure 20.2

b-Lactam Drugs- inhibit cell wall synthesis Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis These enzymes mediate formation of peptide bridges between adjacent stands of peptidoglycan b-lactam ring similar in structure to normal substrate of enzyme Drug binds to enzyme, competitively inhibit enzymatic activity

b-Lactam Drugs Some bacteria produce b-lactamase- enzyme that breaks the critical b-lactam ring b-lactam drugs include: penicillins and cephalosporins

Antibacterial medications that inhibit protein synthesis Target ribosomes of bacteria Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation Tetracyclines: bind to 30S subunit blocking attachment of tRNA Macrolides: bind 50S subunit and prevents continuation of protein synthesis

Figure 20.4b

Antibacterial medications that inhibit nucleic acid synthesis Target enzymes required for nucleic acid synthesis Fluoroquinolones: inhibit enzymes that maintain the supercoiling of closed circular DNA Rifamycins: block prokaryotic RNA polymerase from initiating transcription

Antibacterial medications injure plasma membrane Polymyxin B: binds to membrane of G- bacteria and alters permeability This leads to leakage of cellular contents and cell death These drugs also bind to eukaryotic cells to some extent, which limits their use to topical applications

Antibacterial drugs that inhibit synthesis of essential metabolites Competitive inhibition by substance that resembles normal substrate of enzyme Sulfa drugs

Antiviral Drugs Very few antiviral drugs approved for use in US Effective against a very limited group of diseases Targets for antiviral drugs are various points of viral reproduction

Nucleoside and Nucleotide analogs Acyclovir- used to treat genital herpes Cidofovir- used for treatment of cytomegaloviral infections of the eye Lamivudine- used to treat Hepatitus B

Antiretrovirals Currently implies, a drug used to treat HIV Tenofovir- nucleotide reverse transcriptase inhibitor Zidovudine- nucleoside analog

Other enzyme inhibitors Zanamivir (Relenza) and Oseltamivir phosphate (Tamiflu)- inhibitors of the enzyme neuominidase Used to treat influenza Indinavir- protease inhibitors

Interferons Cells infected by a virus often produce interferon, which inhibits further spread of the infection Alpha-interferon- drug for treatment of viral hepatitis infections

Antifungal drugs More difficult to find point of selective toxicity in eukaryotes than in prokaryotes Targets of antifungal drugs: Agents affecting fungal sterols Agents affecting fungal cell walls Agents inhibiting nucleic acids

Agents affecting fungal sterols Many antifungals target the sterols in the plasma membrane Polyenes- used in systemic fungal infections, very toxic to kidneys Azoles- used for athlete’s foot and vaginal yeast infections (miconizole)

Agents affecting fungal cell walls primary target of selective toxicity is β-glucan Inhibition of synthesis of this glucan results in an incomplete cell wall, and results in lysis of the cell Caspofungin- first new class of antifungals in 40 years

Agents inhibiting nucleic acids Flucytin- nucleotide analog of cytosine, interferes with the biosynthesis of RNA, and therefore protein synthesis

Antiprotozoan drugs Quinine still used to control malaria Chloroquinone- synthetic derivative has largely replaced it Mefloquinone- used in areas where resistance to chloroquinone has developed Quinacrine- drug of choice for treating protozoan disease, giardiasis

Antihelminthic drugs Praziquantel- used in treatment of tapeworms; kills worms by altering permeability of plasma membranes

Kirby-Bauer method for determining drug susceptibility Bacteria spread on surface of agar plate 12 disks, each with different antimicrobial drug, placed on agar plate Incubated- drugs diffuse outward and kill susceptible bacteria Zone of inhibition around each disk Compare size of zone to chart

Figure 21.10

Resistance to antimicrobial drugs Drug resistance limits use of ALL known antimicrobials Penicillin G: first introduced, only 3% of bacteria resistant Now, over 90% are resistant

How do bacteria become resistant? Spontaneous Mutation: happen as cells replicate Gene Transfer: Usually spread through conjugative transfer of R plasmid

Slowing the emergence and spread of antimicrobial resistance Responsibilities of Physicians: must work to identify microbe and prescribe suitable antimicrobials, must educate patients Responsibilities of Patients: need to carefully follow instructions

Slowing the emergence and spread of antimicrobial resistance 3. Educate Public: must understand appropriateness and limitations of antibiotics ; antibiotics not effective against viruses 4. Global Impacts: organism that is resistant can quickly travel to another country - in some countries antibiotics available on non-prescription basis - antibiotics fed to animals can select for drug- resistant organisms

New Approaches to Antibiotic Therapy Are Needed Scientists work to find new antibiotic targets in pathogens Discovery of new and unique antibiotics is necessary