Micro chapter 12

Cell wall inhibitors

Block synthesis and repair (ex: PCNS and vancomycin)

Nucleic Acids (DNA/RNA) synthesis can be blocked at any step in it's pathway

Block synthesis of nucleotides (building blocks of DNA, RNA) Inhibit replication of DNA, RNA Stop transcription: DNA-->RNA Example: Cipro, AZT

Antibacterial Drugs Targeting DNA or RNA

Fluoroquinolones - Norfloxacin, Ciprofoxacin

Selective Toxicity

Goal of antimicrobial chemotherapy: administer a drug to an infected person, which destroys the infective agent without harming the host's cells (rather hard to achieve this goal)

Considerations in Selecting an Antimicrobial Drug: Three factors must be known

- The nature of the microorganism causing the infection - The degree of the microorganism's susceptibility to various drugs - The overall medical condition of the patient

Interferon (IFN): An Alternative to Artificial Drugs

Antiviral compound produced by cells of the body Often results in serious side effects - flu-like symptoms, depression, fatigue, diarrhea, nausea

Mechanisms of Drug Action

Inhibition of cell wall synthesis- selective Inhibition of nucleic acid structure and function Inhibition of protein synthesis- selective Interference with cell membrane structure or function Inhibition of folic acid synthesis- selective

Antimicrobial Drugs that Block Protein Synthesis

Inhibits protein synthesis by blocking any of the steps in translation: RNA -->protein

Superinfection: cephalosporin

Using a broad-spectrum cephalosporin for a urinary tract infection; destroys lactobacilli in the vagina; without the lactobacilli, Candida albicans can proliferate and cause a yeast infection

Therapeutic Index

What is the best drug to use? Lowest risk of side effects versus Highest probability of killing the pathogen Higher T.I. are better

superinfection

When beneficial species are destroyed, microbes that were once kept in small numbers can begin to overgrow and cause disease

Antibacterial Drugs Targeting Cell Membranes

Polymyxins, Daptomycin

Semisynthetic drugs

drugs that are chemically modified in the laboratory after being isolated from natural sources

Quinine

extracted from the bark of the cinchona tree

Biota

normal colonists or residents of healthy body surfaces - Usually harmless or beneficial bacteria - Small number can be pathogens

Antimicrobial Drugs that Affect the Bacterial Cell Wall

- Active cells must constantly synthesize new peptidoglycan and transport it to the proper place in the cell envelope - Penicillins and cephalosporins react with one or more of the enzymes required to complete this process - Known as Bactericidal antibiotics

Antiviral drugs: 3 modes of action

- Barring penetration of the virus into the host cell (Tamiflu) - Blocking the transcription (blocks DNA synthesis) and translation of viral molecules (Acyclovir, AZT) - Preventing the maturation of viral particles/release - Protease inhibitors

Interactions Between Microbes and Drugs: The Acquisition of Drug Resistance

- Can be intrinsic (will be resistant to any antimicrobial it produces) or acquired - Microbes become newly resistant to a drug after: Spontaneous mutations in critical chromosomal genes Acquisition of entire new genes or sets of genes via transfer from another species (plasmids called resistance (R) factors) - Specific Mechanisms of Drug Resistance

The Origins of Antimicrobial Drugs

- Chemists have created new drugs by altering the structure of naturally occurring antibiotics - Also Searching for metabolic compounds with antimicrobial effects in species other than bacteria and fungi (plants and animals)

Antimicrobial Drugs that Disrupt Cell Membrane Function

- Damaged membrane invariably results in death from disruption in metabolism or lysis - Specificity for particular microbial groups based on differences in the types of lipids in their cell membranes - Toxic to humans due to similarities in membrane structure - Polymyxins, Nystatin

Considerations in Selecting an Antimicrobial Drug: Identifying the Agent

- Direct examination of body fluids, sputum, or stool is a rapid initial method - The choice of drug will be based on experience with drugs that are known to be effective against the microbe: the "informed best guess"

Goal of antimicrobial drugs

- Disrupt the cell processes or structures of bacteria, fungi, and protozoa - Or inhibit virus replication

Antihelminthic Drug Therapy

- Flukes, tapeworms, and roundworms have greater similarities to human physiology - Using drugs to block their reproduction is usually not successful in eradicating adult worms - Most effective drugs immobilize, disintegrate, or inhibit the metabolism of all stages of the life cycle ex mebendazole, thiabendazole

Fluoroquinolones - Norfloxacin, Ciprofoxacin

- High potency, easily absorbed - Broad spectrum - Inhibit a wide variety of gram-positive and gram-negative bacterial species even in minimal concentrations

Fungal cells are eukaryotic, so present special problems

- Majority of chemotherapeutic drugs are designed to act on bacteria and are ineffective for fungal infections - Similarities between fungal and human cells- toxicity to humans - Lengthy duration of treatment - Nystatin, amphotericin B, Griseofulvin, miconazole

The Cephalosporin Group of Drugs

- Newer group - similar to penicillin - Currently account for a majority of all antibiotics administered - Broad spectrum - Most resistant to penicillinase - Fewer allergic reactions Other drugs targeting cell wall: bacitracin, vancomycin

Aminoglycoside Drugs

- Products of various species of soil actinomycetes in the genera Streptomyces and Micromonospora - Relatively broad spectrum because they inhibit protein synthesis - Streptomycin, Gentamicin, Tetracyclines, Erythromycin, Chloramphenicol, Clindamycin

Polymyxins, Daptomycin

- used in limited circumstances for infections not responsive to other drugs - toxic to kidneys

Interferon (IFN): An Alternative to Artificial Drugs: Known therapeutic benefits

-- Reducing the time of healing and some of the complications in certain infections - Preventing or reducing some symptoms of cold and papillomaviruses (HPV) - Slowing the progress of certain cancers

Penicillin

1St antibiotic - discovered by Fleming

Survey of Major Antimicrobial Drug Groups

About 260 different antimicrobial drugs Classified in 20 drug families Largest number of antimicrobial drugs are for bacterial infections

Antibacterial Drugs Targeting Protein Synthesis

Aminoglycoside Drugs

Metronidazole (Flagyl)

Amoebicide can also apply to infections by Giardia lamblia and Trichomonas vaginalis

Testing for the Drug Susceptibility of Microorganisms

Kirby Bauer Disc Diffusion Test

Disk Diffusion Assays

Kirby-Bauer Standardized conditions Zones of inhibition Larger zone indicates more susceptible Smaller zone indicates more resistant

Chemotherapy for Other Protozoan Infections

Metronidazole (Flagyl)

Penicillin group

Most end in the suffix -cillin All consist of three parts: a thiazolidine ring, a beta-lactam ring, and a variable side chain

Interactions Between Drug and Microbe

Most interfere with the function of enzymes required to synthesize or assemble macromolecules or destroy structures already formed in the cell

New Approaches to Antimicrobial Therapy

Often researchers try to find new targets in the bacterial cell and custom-design drugs that aim for them Targeting iron-scavenging capabilities of bacteria

Superinfection: Oral therapy

Oral therapy with tetracyclines, clindamycin, and broad-spectrum penicillins and cephalosporins is associated with antibiotic-associated colitis

Antimalarial Drugs

Quinine and Its Relatives

Antiviral Chemotherapeutic Agents: Selective toxicity

almost impossible to achieve because a single metabolic system is responsible for the well-being of both virus and host

narrow spectrum (limited spectrum)

antimicrobials effective against a limited array of microbial types

broad spectrum (extended spectrum)

antimicrobials effective against a wide array of microbial types

chemotherapeutic drug

any chemical used in the treatment, relief, or prophylaxis of disease

Antiviral Chemotherapeutic Agents: Several antiviral drugs

been developed that target specific points in the infectious cycle of viruses

Folic acid synthesis

block pathways and inhibit metabolism (ex: sulfa drugs)

Sulfa drugs

block the enzyme need for folic acid synthesis, thus DNA cannot be synthesized.

Sulfonamides (Sulfa - 1st antimicrobial)

blocks DNA synthesis by competitive inhibition

Cell membrane

cause loss of selective permeability (ex: polymyxins and daptomycin)

The Origins of Antimicrobial Drugs: Antibiotics

common metabolic products of aerobic bacteria and fungi - more than ½ of antibiotics come from: Bacteria: Streptomyces and Bacillus Molds: Penicillium and Cephalosporium

Chemotherapeutic agents

described with regard to their origin, range of effectiveness, and whether they are naturally produced or chemically synthesized

broad-spectrum antimicrobial

destroys both infectious agents but also some beneficial species

Probiotics

ingesting live microorganisms

Prebiotics

ingesting nutrients that encourage the growth of beneficial microbes soybean, onion, chicory root, asparagus etc

Protein synthesis

inhibitors acting on ribosomes

DNA/RNA

inhibits replication and transcription

Disadvantage: Penicillin

some are destroyed by bacteria that produce penicillinase (cleaves beta-lactam ring). Another disadvantage: allergies

Antibiotics

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

Folic acid

synthesized by the bacterial cell and necessary for DNA synthesis. In eukaryotes folic acid is supplied in the diet

Synthetic drugs

the use of chemical reactions to synthesize antimicrobial compounds in the laboratory

Antimicrobial chemotherapy

the use of chemotherapeutic drugs to control infection

Drugs should be selectively toxic

they kill or inhibit microbial cells without damaging host tissues

Prokaryotic ribosomes are different from eukaryotic ribosomes

thus a drug affecting a bacterial cell will not affect a eukaryotic cell (you) - Good example of Selective Toxicity

Prophylaxis

use of drug to prevent imminent infection of a person at risk