Antimicrobial Chemotherapy

Exam 2

Paul Ehrlich

Father of antimicrobial chemotherapy

Coined the term “magic bullet”

Developed a treatment for syphilis in 1909, Compound 606 or Salvarsan

Alexander Fleming

Discovered penicillin in 1928

Penicillium notatum mold in a petri dish containing a staphylococcus culture after a 2-week vacation

Received the Nobel Prize in Physiology or Medicine in 1945

History of Antimicrobial Chemotherapy

“Golden Age” of antimicrobial discovery (1940s – 1960s)

The introduction of modern drugs to control infections was a medical revolution in the 1940s

Antimicrobial drugs have reduced the incidence of certain infections- Have not eradicated infectious diseases though

Today, doctors are worried that we are dangerously close to a post-antibiotic era-

Drugs we have are no longer effective

Goal of antimicrobial Chemotherapy

Administer a drug to an infected person that destroys the infective agent without harming the host’s cells

An antimicrobial Chemotherapy must be able to

Be easy to administer and reach the infectious agent anywhere in the body

Be absolutely toxic to the infectious agent

Be absolutely nontoxic to the host

Remain active in the body as long as needed

Be safely and easily broken down and excreted

General Characteristics of Antimicrobial Drugs

Selective toxicity

Therapeutic dose

Toxic dose-

Therapeutic index

Prophylaxis

A drug given prior to infection- prevention of infection

Antimicrobial Chemotherapy

the use of drugs to control infection

Antimicrobials

all-inclusive term for any antimicrobial drug, regardless of its origin

Antibiotics

substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms; 

generally the term is used for drugs targeting bacteria and not other types pf microbes

Semisynthetic Drugs

Drugs that are chemically modified in the laboratory after being isolate from natural sources

Synthetic Drugs

Drugs produced entirely by chemical reactions

Before Antimicrobial Chemotherapy can Begin

the identity of the microorganism causing the infection must be known

the degree of the microorganisms susceptibility or sensitivity to various drugs must be known

the overall medical condition of the patient must be known

Identification of infectious agents

Should occur before antimicrobial drugs are given

Direct examination of body fluids, sputum, or stool samples is a rapid method for detection

Doctors often begin therapy on the basis of immediate findings and informed guesses

Epidemiological statistics may be required

Types of Spectrum activity of drugs

Broad and Narrow

Broad-Spectrum Drugs

effective against more than one group of bacteria

Narrow-Spectrum Drugs

target a specific group of bacteria

We have been able to alter some naturally occurring drugs to broaden their spectrum

Therapeutic Index Definition

the ratio of the dose of the drug that is toxic to humans as compared to its minimum therapeutic dose

The smaller the ratio, the greater the potential for toxic drug reactions- TI = 1.1 is a risky choice

The drug with the highest therapeutic index has the widest margin of safety- TI = 10 is a safer choice

How is the Effectiveness of a Drug expressed

Minimal Inhibitory Concentration (MIC)

Minimal lethal Concentration (MLC

Minimal Inhibitory Concentration

Lowest concentration of a drug that inhibits growth of a pathogen

Minimal Lethal Concentration

Lowest concentration of drug that kills pathogen

Mechanisms of Action of antibacterial Drugs

Inhibitors of cell wall synthesis

Protein synthesis inhibitors

Metabolic antagonists

Nucleic acid synthesis inhibition

Inhibitors of Cell wall synthesis

Attacks cell walls of bacteria cells

Penicillin, Cephalosporins, Vancomycin

Penicillin’s Characteristics/Features

Most are 6-aminopenicillanic acid derivatives and differ in side chain attached to amino group

Most crucial feature of molecule is the β-lactam ring (Essential for bioactivity)

Many penicillin resistant organisms produce β-lactamase (penicillinase) which hydrolyzes a bond in this ring

Resistance to penicillins, including its semisynthetic analogs is an issue

Penicillin Mode of Action

Blocks the enzyme that catalyzes transpeptidation (formation of cross-links in peptidoglycan)

Prevents the synthesis of complete cell walls leading to the lysis of cell

Acts only on growing bacteria that are synthesizing new peptidoglycan

Naturally Occurring Penicillins

Penicillin V and G (both narrow spectrum)

Semisynthetic Penicillins

Broader Spectrum

Cephalosporins characteristics

Cell wall synthesis inhibitor

Structurally and functionally similar to penicillins

Broad-spectrum antibiotics that can be used by most patients that are allergic to penicillin

Categories based on their spectrum of activity

Vancomycin

Inhibit cell wall synthesis

Important for treatment of antibiotic-resistant staphylococcal and enterococcal infections- MRSA & VRE

Previously considered “drug of last resort” so rise in resistance to vancomycin is of great concern

Protein Synthesis Inhibitors Characterisitcs

Many antibiotics bind specifically to the bacterial ribosome- Binding can be to 30S (small) or 50S (large) ribosomal subunit

Other antibiotics inhibit a step in protein synthesis- Aminoacyl-tRNA binding, Peptide bond formation, mRNA reading, translocation

Protein Synthesis Inhibitors

Aminoglycoside antibiotics

Tetracyclines

Macrolides

Aminoglycoside Antibiotics

Protein Synthesis inhibitor

Large group, all with a cyclohexane ring, amino sugars

Bind to 30S ribosomal subunit, interfere with protein synthesis by directly inhibiting the process and by causing misreading of the mRNA

Resistance and toxicity

Tetracyclines

Protein Synthesis Inhibitor

All have a four-ring structure to which a variety of side chains are attached

Are broad spectrum, bacteriostatic

Combine with 30S ribosomal subunit- Inhibits binding of aminoacyl-tRNA molecules to the A site of the ribosome

Macrolides

Protein Synthesis Inhibitor

Contain 12- to 22-carbon lactone rings linked to one or more sugars

Erythromycin- Broad spectrum, usually bacteriostatic- Binds to 23S rRNA of 50S ribosomal subunit

Inhibits peptide chain elongation

Used of patients allergic to penicillin

Metabolic Antagonists Characteristics

Act as antimetabolites that  Antagonize or block functioning of metabolic pathways by competitively inhibiting the use of metabolites by key enzyme

Are Structural Analogs that are structurally similar to, and compete with, naturally occurring metabolic intermediates- Block normal cellular metabolism

Sulfonamides

Structurally related to sulfanilamide, a p-aminobenzoic acid (PABA) analog

PABA used for the synthesis of folic acid and is made by many pathogens

Sulfa drugs are selectively toxic due to competitive inhibition of folic acid synthesis enzymes

Trimethoprim

Synthetic antibiotic that also interferes with folic acid production

 Broad spectrum

Can be combined with sulfa drugs to increase efficacy of treatment

Combination blocks two steps in folic acid pathway

Has a variety of side effects including abdominal pain and photosensitivity reactions

Nucleic Acid Synthesis Inhibitors Characteristics

A variety of mechanisms

Block DNA replication- Inhibition of DNA polymerase, Inhibition of DNA helicase

OR

Block transcription- Inhibition of RNA polymerase
Drugs not as selectively toxic as other antibiotics because bacteria and eukaryotes do not differ greatly in the way they synthesize nucleic acids

Nucleic Acid Synthesis Inhibitors

Quinolones

Quinolones

Nucleic Acid Synthesis Inhibitior

Broad-spectrum, synthetic drugs containing the 4-quinolone ring

Nalidixic acid first synthesized quinolone (1962)

Act by inhibiting bacterial DNA-gyrase and topoisomerase II

Broad spectrum, bactericidal, wide range of infections

Antifungal Drugs

Fewer effective agents because of similarity of eukaryotic fungal cells and human cells

Many have low therapeutic index and are toxic

Easier to treat superficial mycoses than systemic infections- Combination of drugs might be used

Superficial Mycoses

Topical and oral

Disrupt membrane permeability and inhibit sterol synthesis

Disrupts mitotic spindle; may inhibit protein and DNA synthesis

Treating Systemic Mycoses

Difficult to control and can be fatal

Three common drugs

Amphotericin B- Bind sterols in membranes

5-flucytosine- Disrupts RNA function

Fluconazole- Low side effects, used prophylactically

Antiviral Drugs Characteristics

Drug development has been slow because it is difficult to specifically target viral replication

Drugs currently used inhibit virus-specific enzymes and life cycle processes

Antiviral Drugs

Tamiflu

Anti-HIV Drugs

Tamiflu

Anti-influenza agent

A neuraminidase inhibitor

Though not a cure for influenza, has been shown to shorten course of illness

Anti-HIV Drugs

Reverse transcriptase (RT) inhibitors- Nucleoside RT inhibitors, Non-nucleoside RT inhibitors

Protease inhibitors- Mimic peptide bond that is normally attacked by the protease

Fusion inhibitors- Prevent HIV entry into cells

Most successful are drug cocktails to curtail resistance

Antiprotozoal Drugs

The mechanism of drug action for antiprotozoal drugs is not known

Examples of available drugs:

Drugs which inhibit bacterial protein synthesis can be used

Chloroquine and mefloquine – malaria

Metronidazole – Entamoeba infections

Atovaquone – Pneumocystis carinii and Toxoplasma gondii

Drug Resistance

An adaptive response in which microorganisms begin to tolerate an amount of drug that would normally be inhibitory

Due to the genetic versatility and adaptability of microbial populations

Can be intrinsic as well as acquired

How does drug resistance develop

Microbes become newly resistant to a drug after one of the following occurs:

Spontaneous mutations in critical chromosomal genes

Acquisition of entire new genes or sets of genes via horizontal transfer from another species

Genetic changes result in cellular structure/function changes

Natural Selection and Drug Resistance

Development of resistance and its long-term therapeutic consequences:

Any large population of microbes will contain a few cells harboring drug resistance

As long as the drug is not present in the habitat, the genes are not expressed

If the population is exposed to drugs, the drug-resistant population will have a selective advantage.

Offspring inherit the drug resistance

Replacement populations evolve to have the drug-resistant form as the dominant species

Selective Toxicity Definition

Ability of drug to kill or inhibit pathogen while damaging host as little as possible

Therapeutic Dose Definition

Drug level required for clinical treatment

Toxic Dose

Drug level at which drug becomes too toxic for patient (i.e. produces side effects)