ANTIMICROBIAL DRUGS 1

Antimicrobial Drugs

Chemotherapy: The use of drugs to treat a

disease.

▪ Antimicrobial drugs: Interfere with the growth of

microbes within a host.

▪ Antibiotic: Of biological origin. Produced by a

microbe, inhibits other microbes.

▪ Chemotherapeutic agent: synthetic chemicals

▪ Today distinction blurred → many newer

"antibiotics" are biological products that are

▪ chemically modified or

▪ chemically synthesized

The History of Chemotherapy

▪ Paul Ehrlich and Sahachiro

Hata developed Salvarsan

(Arsphenamine) against

syphilis in 1910: The

concept of chemotherapy to

treat microbial diseases was

born.

▪ Sulfa drugs (sulfanilamide)

discovered in 1932 →

against Gram+ bacteria

CummingsThe History of Chemotherapy cont.

1928: Fleming discovered

penicillin

1940: Howard Florey and Ernst

Chain performed first clinical

trials of penicillin.

Features of Antimicrobial Drugs

▪ Selective toxicity: Drug kills pathogens without

damaging the host.

▪ Therapeutic index: ratio between toxic dose and

therapeutic dose – or ratio of LD50 to ED50

High therapeutic index ⇒ less toxic

▪ Antimicrobial action – Bacteriostatic vs. bactericidal

▪ Activity Spectrum – Broad-spectrum vs. narrow-

spectrum

▪ Tissue distribution, metabolism, and excretion –

BBB; Unstable in acid; half-life duration

THE ACTION OF ANTIMICROBIAL DRUGS

Antibacterial Antibiotics

Inhibitors of Cell Wall Synthesis: Penicillin

Natural and semisynthetic penicilins contain β-lactam ring

Natural penicillins produced by Penicillium are effective

against Gram + cocci and spirochetes

Semisynthetic penicillins: made in laboratory by adding

different side chains onto β-lactam ring ⇒ penicillinase

resistant and broader spectrum of activity

Penicillin cont.

Penicillinase (β-lactamase): bacterial enzyme that

destroys natural penicillins

Penicillinase resistant penicillins: methicilin replaced

by oxacilin and nafcilin due to MRSA

Extended-spectrum penicilins: Ampicilin, amoxicilin;

new: carboxypenicilins and ureidopenicillins (also good

against P. aeruginosa)

Cephalosporins

Fungi of genus

Cephalosporium

⇒ 4 Generations of

cephalosporins

1. First-generation: Narrow spectrum, gram-positive

2. Second-generation: Extended spectrum includes

gram-negative

3. Third-generation: Includes pseudomonads; mostly

injected, some oral.

4. Fourth-generation: Most extended spectrum

Cephalosporins cont.

Structure and mode of action resembles penicilins

1. More stable to

bacterial

β-lactamases than

penicilins

2. Broader spectrum

⇒ used against

penicillin-resistant

strains

Vancomycin

▪ Glycopeptide from Streptomyces

▪ Inhibition of cell wall synthesis

▪ Used to kill MRSA

▪ Emerging Vancomycin

resistance: VRE and VRSA

Antifungal Drugs

▪ Polyenes, such as nystatin and amphotericin B,

for systemic fungal infections. Inhibition of

ergosterol synthesis ⇒ fungicidal. Nephrotoxic

▪ Griseofulvin from Penicillium. Systemic/oral.

Binds to tubulin ⇒

For Tineae

Antiviral Drugs

Nucleoside analogs inhibit DNA synthesis

Acyclovir and newer derivatives: Selective inhibition

of herpes virus replication. Acyclovir conversion to

nucleotide analog only in virus infected cells ⇒

very little harm to uninfected cells!

Antiviral Drugs for Treating HIV/AIDS:

HAART

1. NRTIs and NNRTIs

2. Protease Inhibitors

3. Fusion Inhibitors

4. Integrase Inhibitors

HIV protease cleaves viral polypeptide

into functional proteins

Protease inhibition ⇒ HIV cannot

mature and noninfectious viruses are

produced.Antiprotozoan and Antihelminthic Drugs

Examples of Antiprotozoan:

▪ Chloroquine: Malaria

▪ Quinacrine: Giardia

▪ Metronidazole (Flagyl): Vaginitis, anaerobic bacteria

Examples of Antihelminthic:

▪ Niclosamide and praziquantel: Tapeworm

▪ Mebendazole: broadspectrum antihelmintic

▪ Ivermectin: nematodes, mites, lice . . .

Antibiotic Assays to Guide Chemotherapy

Agar Disk Diffusion Method determines

susceptibility of an organism to a series of

antibiotics: Kirby-Bauer test

More sophisticated methods available for clinical

labs

Drug Resistance

Penicillin G resistance of S. aureus from 3% to >

90%

Multidrug-resistant S. aureus = MRSA or

“super-bug”

Vancomycin-resistance →

Multi drug resistant TB = MDR-TB

Evolution of drug resistance:

▪ Vertical evolution due to spontaneous

mutation

▪ Horizontal evolution due to gene transfer

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

Read Clinical Focus:

Antibiotics in Animal Feed

Linked to Human Disease (p. 577)

▪ Misuse of antibiotics selects for resistance mutants.

Misuse includes

▪ Using outdated or weakened antibiotics

▪ Using antibiotics for the common cold and other

inappropriate conditions

▪ Using antibiotics in animal feed

▪ Failing complete the prescribed regimen

▪ Using someone else's leftover prescription