Antimicrobial Drugs

Fading Miracle?

BLS 206 Lecture

Hoza, A . S

Ehrlich’s Magic Bullets

• 1906: Paul

Ehrlich discovered

Salvarsan 606

• 1930s: sulfa drugs

discovered

Fleming and Penicillin

TERMINOLOGIES

Chemotherapy

• The use of drugs to treat a disease

• Selective toxicity:

– A drug that kills harmful microbes

without damaging the host

Terminologies

Antibacterial spectrumRange of activity of an antibiotic

A broad spectrumAntibiotic that can inhibit wide range of G- positive and G-

negative bacteria e.g. Carbapenems, 3-4th generation

cephalosporins, quinolones

A narrow spectrumAntibiotic that is active only against a limited number of

bacteria e.g. penicillin G, 1-2nd generation cephalosporins,

oxazolidone

Terminologies

Bacteriostatic activity

Level of antimicrobial activity that inhibits the

growth of bacteria

Minimum inhibitory concentration (MIC)

The lowest concentration that inhibits the growth

of bacterial population

Bactericidal activity

Minimum bactericidal concentration (MBC)

The lowest concentration that kills 99.9% of

the bacterial population

Antibiotic synergism

Combination of antibiotics have enhanced activity

when tested together compared with each antibiotic

alone (e.g. 2 + 2 = 6)

e.g. ampicillin+gentamicin in entercoccal carditis

Additive effect

Combination of antibiotics has an additive effect

(e.g. 2 + 2 = 4)

e.g. combination of two ß-lactam antibiotics

Antibiotic antagonism

Combination in which the activity of one antibiotic

interferes with the activity of the other (e.g. 2 + 2 < 4)

Antibiotic combinations

Effects of Combinations of Drugs

• Synergism occurs when the effect of two drugs

together is greater than the effect of either alone.

• Antagonism occurs when the effect of two drugs

together is less than the effect of either alone.

Effects of Combinations of Drugs

Combined antibacterial therapy

Antibiotic/Antimicrobial

• Antibiotic:

– Chemical produced by a microorganism that kills or inhibits the growth of another microorganism

• Antimicrobial agent:

– Chemical that kills or inhibits the growth of microorganisms

Antimicrobial Agents• Disinfectant:

•antimicrobial agent used only on inanimate

objects

• Chemotherapeutic agent:

•antimicrobial agent that can be used internally

• Bactericidal:

•agent that kills bacteria

• Bacteriostatic:

•agent that inhibits the growth of bacteria

Microbial

Sources of

Antibiotics

Antibiotic Spectrum of Activity

• No antibiotic is effective against all microbes

Mechanisms of Antimicrobial Action

• Bacteria have their own enzymes for

– Cell wall formation

– Protein synthesis

– DNA replication

– RNA synthesis

– Synthesis of essential metabolites

Mechanisms of Antimicrobial Action

• Viruses use host enzymes inside host cells

• Fungi and protozoa have own eukaryotic enzymes

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

Modes of Antimicrobial Action

Basic mechanisms of antibiotics

Basic mechanisms of antibiotic action

(1) Disruption of bacterial cell wall

ß-lactam antibiotics

Penicillins, cephalosporins and cephamycins,

carbapenems and monobactams, ß-lactamase inhibitor/ß-

lactam combinations

Glycopeptides

Vancomycin

Polypeptides

Bacitracin, polymyxins

Drugs used for treatment of mycobacterial infections

Isoniazid, ethinamide, ethambutol, cycloserine

Bacterial cell wall of G+ (A) and G- (B) bacteria

Gram-positive and Gram-negative bacteria

2. Inhibition of protein synthesis

Acting at 30S ribosomesAminoglycosides

Tetracyclines

Acting at 50S ribosomesChloramphenicol

Macrolides

Clindamycin

Streptogramins

Oxazolidones

3. Inhibition of nucleic acid synthesis

Acting on DNA replication

Quinolones

Metronidazole

Acting on RNA synthesis

Rifampin

Rifabutin

4. Antimetabolites

Sulfonamides

Dapsone

Trimethoprim

Paraaminosalicylic acid

Antimicrobial Agents

Antimicrobial Agents

Antimicrobial Agents

• Penicillin (over 50 compounds)

– Share 4-sided ring (ß lactam ring)

• Natural penicillins

• Narrow range of action

• Susceptible to penicillinase (ß lactamase)

Antibacterial Antibiotics Inhibitors of Cell Wall

Synthesis

Prokaryotic Cell Walls

Gram positive cell

wallGram negative cell

wall

Penicillins

Figure 20.6

Penicillinase (b Lactamase)

Figure 20.8

• Penicilinase- resistant penicillins

• Carbapenems: very broad spectrum

• Monobactam: Gram negative

• Extended- spectrum penicillins

• Penicillins + b-lactamase inhibitors

Semisynthetic Penicillins

• Cephalosporins

– 2nd, 3rd, and 4th

generations more

effective against

gram-negatives

Other Inhibitors of Cell Wall Synthesis

Figure 20.9

• Polypeptide antibiotics

– Bacitracin

• Topical application

• Against gram-positives

– Vancomycin

• Glycopeptide

• Important "last line" against antibiotic resistant

S. aureus

Other Inhibitors of Cell Wall Synthesis

Other Inhibitors of Cell Wall Synthesis

• Antibiotics effective against

Mycobacteria:

– interfere with mycolic acid

synthesis or incorporation

– Isoniazid (INH)

– Ethambutol

• Broad spectrum, toxicity problems

• Examples

– Chloramphenicol (bone marrow)

– Aminoglycosides: Streptomycin, neomycin,

gentamycin (hearing, kidneys)

– Tetracyclines (Rickettsias & Chlamydia; GI tract)

– Macrolides: Erythromycin (gram +, used in

children)

Inhibitors of Protein Synthesis

• Polymyxin B (Gram negatives)

– Topical

– Combined with bacitracin and neomycin

(broad spectrum) in over-the-counter

preparation

Injury to the Plasma Membrane

• Rifamycin

– Inhibits RNA synthesis

– Antituberculosis

• Quinolones and fluoroquinolones

– Ciprofloxacin

– Inhibits DNA gyrase

– Urinary tract infections

Inhibitors of Nucleic Acid Synthesis

– Sulfonamides (Sulfa drugs)

• Inhibit folic acid synthesis

• Broad spectrum

Competitive Inhibitors

Figure 5.7

Antifungal Drugs

• Fungi are eukaryotes

• Have unique sterols in

their cell walls

• Pathogenic fungi are

often outside the body

Antiviral Drugs

• Viruses are composed of nucleic acid, protein

capsid, and host membrane containing virus proteins

• Viruses live inside host cells and use many host

enzymes

• Some viruses have unique enzymes for DNA/RNA

synthesis or protein cutting in virus assembly

Figure 20.16a

Antiviral Drugs

Nucleoside and Nucleotide Analogs

Figure 20.16a

Figure 20.16b, c

Analogs Block DNA Synthesis

• Inhibit assembly

– Indinavir (HIV)

• Inhibit attachment

– Zanamivir (Influenza)

• Inhibit uncoating

– Amantadine (Influenza)

Antiviral Drugs Enzyme Inhibitors

• Interferons

– prevent spread of viruses to new cells (Viral

hepatitis)

• Natural products of the immune system in viral

infections

Antiviral Drugs Enzyme Inhibitors

Antiprotozoan Drugs

• Protozoa are eukaryotic

cells

• Many drugs are

experimental and their

mode of action is unknown

Antihelminthic Drugs

• Helminths are

macroscopic

multicellular eukaryotic

organisms:

– tapeworms,

– roundworms,

– pinworms,

– hookworms

• Prevent ATP generation (Tapeworms)

• Alters membrane permeability (Flatworms)

• Neuromuscular block (Intestinal roundworms)

• Inhibits nutrient absorption (Intestinal roundworms)

• Paralyzes worm (Intestinal roundworms)

Antihelminthic Drugs

Measuring Antimicrobial Sensitivity

• E Test

• MIC: Minimal

inhibitory

concentration

Measuring Antimicrobial Sensitivity: Disk Diffusion

Penicillin