Antimicrobial Drugs

Antimicrobial Drugs

Chemotherapy

Antimicrobial drugs Interfere with

the growth of microbes within a host
Antibiotic

The use of drugs to treat a disease

Substance produced by a microbe that, in

small amounts, inhibits another microbe

Selective toxicity

A drug that kills harmful microbes without

damaging the host

Historical Perspective

Treatment hopeless before 1935

Paul Ehrlich, early 20th century

Fleming -- 1929

Penicillin -- first therapeutic use

Waksman -- 1944

Penicillin discovered -- gram positives

Florey -- 1940

Father of chemotherapy

Streptomycin -- gram negatives

1947 -- Chloramphenicol -- broad spectrum

1947 - present -- many

1928 Fleming
discovered
penicillin,
produced by
Penicillium.
1940 Howard
Florey and
Ernst Chain
performed first
clinical trials of
penicillin.

Figure 20.1

Properties of an ideal antibiotic

broad spectrum
stable--long shelf life
soluble in body fluids
stable toxicity
Nonallergenic
reasonable cost
selectively toxic
not likely to induce bacterial resistance

Major genera that produce clinically

useful antibiotics

Bacillus
Streptomyces
Cephalosporium
Penicillium

Major targets of antimicrobial activity

Cell wall synthesis

penicillins, cephalosporins (beta-lactamase producing

bacteria resistant to both, require active cell wall
synthesis in actively growing cultures), bacitracin
Cell membrane function

amphotericin B (no growth requirement, changes membrane

permeability by binding to sterols in fungal membranes,
more side effects since membranes similar in all cells)
Protein synthesis

Aminoglycides, tetracyclines, chloramphenicol

Major targets of antimicrobial activity

DNA synthesisTranslation (mRNA--> protein):

Transcription: rifampin (TB), actinomycin D
Block movement of ribosome along mRNA: streptomycin,
tetracycline
Prevent peptide bond formation by binding to ribosome:
chloramphenicol, erythromycin
Antimetabolites (structural analogs of natural substances
important in metabolism): PASA, sulfa drugs, INH
PASA very similar in structure to PABA, required by bacteria
(but not human cells) for synthesis of folic acid
When PASA is used in synthesis of folic acid, results in
nonfuctional folic acid analog and bacterial cell dies

Spectrum of Activity

The Action of Antimicrobial Drugs

The Action of Antimicrobial

Drugs

Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis

Penicillin

Natural penicillins

Semisynthetic penicillins

Penicilinase-resistant penicillins

Extended-spectrum penicillins

Penicillins + -lactamase inhibitors

Carbapenems

Monobactam

Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis

Cephalosporins

2nd, 3rd, and 4th generations more effective against

gram-negatives

Polypeptide antibiotics

Bacitracin

Topical application
Against gram-positives

Vancomycin

Glycopeptide
Important "last line" against antibiotic resistant S.
aureus

Antibacterial Antibiotics
Inhibitors of Protein Synthesis

Chloramphenicol

Broad spectrum

Binds 50S subunit, inhibits peptide bond formation

Aminoglycosides

Streptomycin, neomycin, gentamycin

Broad spectrum

Changes shape of 30S subunit

Antibacterial Antibiotics
Inhibitors of Protein Synthesis

Tetracyclines

Broad spectrum

Macrolides

Gram-positives

Interferes with tRNA attachment

Binds 50S, prevents translocation

Erythromycin

Gram-positives

Binds 50S, prevents translocation

Disk-Diffusion Test

Figure 20.17

Definitions

MIC
Minimal inhibitory
concentration
MBC
Minimal bactericidal
concentration

Broth Dilution Test

Figure 20.19

Antibiotic Resistance

A variety of mutations can lead to antibiotic

resistance.

Mechanisms of antibiotic resistance

1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug

Resistance genes are often on plasmids or

transposons that can be transferred between
bacteria.

Antibiotic Resistance

Misuse of antibiotics selects for

resistance mutants. Misuse includes:

Using outdated, weakened antibiotics

Using antibiotics for the common cold and
other inappropriate conditions
Use of antibiotics in animal feed
Failure to complete the prescribed regimen
Using someone else's leftover prescription

Figure 20.20

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

Figure 20.22

The Future of
Chemotherapeutic Agents

Antimicrobial peptides

Broad spectrum antibiotics from plants and animals

Squalamine (sharks)

Protegrin (pigs)

Magainin (frogs)

Antisense agents

Complementary DNA or peptide nucleic acids that

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