Chapter 20: Antimicrobial drugs

Selective toxicity

selectively finding and destroying pathogens without damaging the host

Chemotherapy

the use of chemicals to treat a disease

Antibiotic (AKA antibacterials)

a type of antimicrobial drug

it is a substance produced by a microbe that, in small amounts, inhibits another microbe

Antimicrobial drugs

synthetic substances that interfere with the growth of microbes

Who discovered penicillin in 1928 and produced Penicillium?

Fleming

1932: Prontosil red dye is a compound, sulfanilamide-containing dye used widely in WWII for ___________________ infections.

streptococcal

The first clinical trials of penicillin was in what year?

1940

Antibiotic resistance

formerly effective medications have less and less impact on bacteria

A growing problem today

Antibiosis: Figure 20.1

Representative Sources of Antibiotics: Table 20.1

More than half of our antibiotics are produced by species of ________________________

Streptomyces

Narrow spectrum of microbial activity

drugs that affect a narrow range of microbial types

Broad-spectrum antibiotics

affect a bread range of gram positive or gram negative bacteria

Superinfection

overgrowth of normal microbiota that is resistant to antibiotics

The spectrum of activity of antibiotics and other antimicrobial drugs: Table 20.2

List the five ways of action of antimicrobial drugs

1. Inhibiting the cell wall synthesis

2. Inhibiting protein synthesis

3. Injuring the plasma membrane

4. Inhibiting nucleic acid synthesis

5. Inhibiting the synthesis of essential metabolites

Antimicrobial drugs are either bacteri______ or bacteri_________

bactericidal or bacteriostatic

What type of antimicrobial drug kills microbes directly?

bactericidal

What type of antimicrobial drug prevents microbes from growing?

bacteriostatic

Major action modes of antibacterial drugs: Figure 20.2

Inhibition of cell wall synthesis: How and what drugs are involved?

Penicillins, cephalosporins, bacitracin, vancomycin, bacitracin, antimycobacterial antibiotics

Prevent the synthesis of peptidoglycan of the cell wall

Inhibition of protein synthesis: How and what drugs are involved?

Chloramphenicol, tetracylines, streptomycin, erythromycin, azithromycin

Target bacterial cells 70S ribosomes

Adverse effects: Eukaryotic organelle mitochondria has 70S ribosomes and can have an affect on the host

Inhibition of protein synthesis by antibiotics; figure 20.4

Injuring the plasma membrane: How and what drugs are involved?

Polypeptide antibiotics = Polymyxin B

Changes the bacterial cell membrane permeability

Antifungal drugs like amphotericin B, miconazole, ketoconazole =

Combine with membrane sterols in the fungal plasma membrane and disrupts

Bacteria lack sterols therefore not effective

Inhibiting nucleic acid synthesis: How and what drugs are involved?

Quinolones, fluoroquinolones (ciprofloxacin) & rifampin

Interfere with DNA replication and transcription

Inhibiting the synthesis of essential metabolites: How and what drugs are involved?

Sulfanilamide and trimethoprim

Competitively inhibited: Antimetabolites compete with normal substrates for an enzyme

Sulfanilamide competes with para-aminobenzoic acid (PABA) - stopping the synthesis of folic acid

The term penicillin refers to a group of over _____ chemically related antibiotics

50

All penicillin contain a __________ ring

Beta-lactam ring

Types are differentiated by the chemical side chains attached to the ring

Penicillin prevent the _____________ of peptidoglycans, interfering with the cell wall construction (especially gram-__________ bacteria)

cross-linking

gram-positive

Penicillins extracted from cultures of the mold Penicillium are known as __________ penicillins

natural

The prototype compound of all penicillin is known as penicillin ___

G (injected)

Penicillin ____, which is stable in the stomach acids and can be taken orally.

V

Disadvantages to natural penicillins

-Narrow spectrum of activity

-Susceptible to penicillinases (beta-lactamases) which are enzymes produced by many bacteria especially Staphylococcus species

Natural penicillin G

Requires injection

Beta-lactam ring in the center square

Natural penicillin V

Can be taken orally

Beta-lactam ring in the center square

Semisynthetic penicillins: What are they?

Oxacillin and ampicillin

Why make semisynthetic penicillins?

Developed in attempts to overcome the disadvantages of natural penicillins:

1. Interrupt synthesis of the molecule by Penicillium and obtain only the common penicillin nucleus for use

2. Can remove the side chains from the completed natural molecules and then chemically add other side chains that make them more resistant to penicillinase

What makes them semisynthetic?

part of the penicillin is produced by mold and the other part is added synthetically

Which type of semisynthetic is narrow spectrum, only gram positives, but resistant to penicillinase?

oxacillin

Which type of semisynthetic is extended spectrum and targets many gram-negatives?

ampicillin

semisynthetic penicillins: Figure 20.6b

Retention of penicillin G: Figure 20.7

Drug is present in high concentrations in the blood (solid red line) when administered by injection, but disappears quickly.

Taken orally (dotted red) it is destroyed by stomach acid = not effective

Blue and purple lines: Penicillin G is combined with compounds procaine and benzathine = possible to improve retention but blood concentration reached is low and the target bacterium needs to be extremely sensitive to the antibiotic.

Effect of penicillinase on penicillins: Figure 20.8

Most common form of resistance to penicillins = breaking the beta-lactam ring

Penicillinase-resistant penicillins: What are they?

Resistance to the plasmid-borne gene for beta-lactamase. Antibiotics that are resistant are:

-Methicillin = organisms terms MRSA; so prevalent that methicillin has been discontinued in the U.S.

-Oxacillin

Extended-spectrum penicillins: What are they?

-To overcome the problem of narrow spectrum activity of natural penicillins, broader-spectrum semisynthetic penicillins created

-Effective against gram-negative bacteria as well as gram-positives

-They are not resistant to penicillinases

-First created were aminopenicillins: ampicillin & amoxicillin

Penicillins plus Beta-lactam inhibitors: A different approach to proliferating penicillinase is to combine penicillins with _______________ acid, a noncompetitive inhibitor of penicillinase

clavulanic acid

Carbapenems

-Class of beta-lactam antibiotics

-Substitute a carbon (C) for a sulfur (S) and add a double bond to the penicillin nucleus.

-Inhibit cell wall synthesis and have an extremely broad spectrum of activity

-Primaxin & doripenem

-Effective for Pseudomonas aeruginosa infections

Monobactam

-New class of antibiotics; synthetic ; single ring instead of the beta-lactam double ring

-Aztreonam = has unusually low toxicity and affects only gram-negative bacteria = pseudomonads and E. coli

Cephalosporins

-Similar nuclei to penicillin; work similar

-Beta-lactam ring differs from penicillin

-Grouped according to their generation of development

-Inhibit cell wall synthesis similar to the way penicillins do

Name the two types of polypeptide antibiotics

Bacitracin and vancomycin

Bacitracin

topical application; works against gram-positives

Vancomycin

Glycopeptide; last line against antibiotic-resistant MRSA

What are the two types of antimycobacterial antibiotics?

-Isoniazid (INH)

-Ethambutol (secondary)

Isoniazid (INH) inhibits the _____________ _______________ synthesis in mycobacteria

mycolic acid

Ethambutol inhibits ________________ of the mycolic acid into the cell wall

incorporation

What are the 8 antibiotic groups that inhibit protein synthesis?

1. Chloramphenicol

2. Aminoglycosides

3. Tetracyclines

4. Glyclyclines

5. Macroglides

6. Streptogramins

7. Oxazolidinones

8. Pleuromutilins

Chloramphenicol

-Inhibits peptide bond formation by binding to the 50S portion of the 70S prokaryotic ribosome

-Synthesized chemically; broad spectrum

-Serious adverse affects: can suppress bone marrow and affect blood cell formation

-Low cost

Aminoglycosides

-Amino sugars linked by glycoside bonds

-Interferes with the initial steps of protein synthesis by changing the shape of the 30S portion of the 70S prokaryotic ribosome

--mRNA is read incorrectly

-Significant against gram-negative bacteria

-Best known is streptomycin

-others: neomycin & gentamicin

-Can cause damage to hearing and also the kidneys (use has declined due to this)

Tetracyclines

-Closely related broad-spectrum antibiotics

-Produced by Streptomyces spp.

-Interfere with the attachment of the tRNA carrying the amino acids to the ribosome at the 30S portion of the 70S ribosome

-Do not interfere with mammalian 70S ribosomes however they do in small amounts enter the host cell making them valuable against rickettsias and chlamydias

-Effective against gram-positive, gram-negative and also penetrate body tissues well

Types: oxytetracycline, chlortetracycline, tetracycline

-Synthetic tetracyclines: docycycline & minocycline

-Treat UTI's, mycoplasma pneumonia, chlamydial & rickettsial infections.

-Suppress the normal intestinal microbiota = GI upset = superinfections called Candida albicans

Glyclyclines

-Broad spectrum; newer class (2000)

-Similar to tetracyclines

-Bacteriostatic

-Best known: tygecycline

-Binds to the 30S ribosomal unit = blocking protein synthesis

-Inhibits rapid efflux

-Slow IV infusion

-Useful against MRSA

Macrolides

-Macrocyclic lactone ring (star-shaped)

-Best known: erythromycin

-Others: azithromycin, clarithromycin

-Narrow spectrum against gram-positives

-Inhibits protein synthesis by blocking the tunnel

-Similar to penicillin G and used as an alternative

-Treats legionellosis, mycoplasma pneumonia, and other infections

Streptogramins

-Synercid: combination of two cycline peptides: quinupristin and dalfopristin (distantly related to macrolides

-Block protein synthesis by attaching to the 50S portion of the ribosome

-Works against gram-positives that are resistant to other antibiotics

Oxazolidones

-New class developed in response to vancomycin resistance (2001)

-Act on the ribosomes by binding to the 50S ribosomal subunit close to the point where it interfaces with the 30S subunit

-Synthetic = resistance is slower to develop

- Linezolid = type to combat MRSA

Pleuromutilins

-New class (2000)

-Interferes with protein synthesis

-First antibiotic for human use = retapamulin, a topical and effective against gram-positives

Lipopeptide

-Daptomycin: gram-positive bacteria only

-Produced by a streptomycete

-Used for skin infections

-Attacks the bacterial cell membrane (affects synthesis)

Polymyxin B

-Bactericidal; topical; effective against gram-negative bacteria

-Combined with bacitracin and neomycin in nonprescription ointments

Rifamycin

-Inhibits mRNA synthesis

-Penetrates tissues; antitubercular activity

-Rifampin

-Structurally related to macrolides

-Treats mycobacteria infections: TB and leprosy

-Side effect: orange-red urine, feces, saliva, sweat and tears

Quinolone & Fluoroquinolones

-1960's: synthetic drug nalidixic acid was developed = first in the quinolone group

-Synthetic and a bactericidal effect by inhibiting an enzyme DNA gyrase

-1980's: prolific group of synthetic quinolones = fluoroguinolones

-Norfloxacin and ciprofloxacin = treats anthrax infections

-Newer group: gemifloxacin and moxifloxacin

-Resistance can develop quickly; broad-spectrum & nontoxic

Sulfonamides

-sulfa drugs

-Inhibit the folic acid synthesis needed for nucleic acid and protein synthesis

-Competitively bind to the enzyme meant for PABA (structurally similar) = blocking folic acid production

-PABA = folic acid precursor

-Combination of trimethoprim and sulfamethoxazole = drug synergism

Many antifungal drugs target the ___________ in the plasma membrane, making it excessively permeable.

sterols (principal type: ergosterol)

Polyenes

-Amphotericin B: produced by Streptomyces & toxic to the kidneys

Azoles

Imidazoles: first type made which includes clotrimazole and miconazole

-No prescription; used topical to treat cutaneous mycoses (athlete's foot, vaginal yeast infections)

Triazole: fluconazole and itraconazole

-Treat systemic fungal infections

Allylamines

-For azole-resistant infections

-Inhibits the biosynthesis of ergosterols

Agents affecting fungal cell walls

-Primary target other than ergosterol is beta-glucan compound

-Echinocandins - inhibits the biosynthesis of beta-glucans = incomplete cell wall and cell lysis

Agents inhibiting nucleic acids

-Flucytosine : cytosine analog interferes with RNA synthesis

Griseofulvin

-Produced by the species Penicillium

-Inhibits microtubule formation = interferes with mitosis and therefore fungal reproduction

-Active against superficial dermatophytic fungal infections of the hair and nails

-Binds to keratin

Tolnaftate

-For athlete's foot

-Alternative to miconazole

Pentamidine

-Anti-Pneumocystis; may bind to DNA

Antiviral drugs: Entry and Fusion Inhibitors

-Drugs that block the initial steps in viral infection: absorption and penetration

-Blocks the receptors on the host cell that bind to the virus

-Block fusion of the virus and cell

Antiviral drugs: Uncoating, Genome Integration & Nucleic Acid Synthesis Inhibition

--Prevent viral uncoating

-Inhibit viral DNA integration into the host genome

-Nucleoside analogs inhibit RNA and DNA synthesis

Antiviral drugs: Interference with Assembly and Release of Viral Particles

-Protease inhibitors: block the cleavage of protein precursors

Antiviral drugs: Exit inhibitors

-Inhibit neuraminidase, an enzyme required for some viruses to bud from the host cell

Antiviral drugs: Interferons

-Produced by viral-infected cells to inhibit further spread of infection

-Imiquimod: promotes interferon production

Antivirals for treating HIV/AIDS

*HIV is an RNA virus; it's reproduction depends on the enzyme reverse transcriptase, which controls the synthesis of RNA from DNA.

-Antiretroviral=a drug is used to treat HIV infection

1. Nucleoside analog is zidovudine

2. Nucleotide analog is tenofovir

3. Non-nucleoside inhibitors is nevirapine

4. Protease inhibitors is atazanavir

5. Integrase inhibitors is raltegravir

6. Entry inhibitors is miraviroc

7. Fusion inhibitors is enfuvirtide

Antiprotozoan drugs

-Quinine and chloroquine treat malaria

-Artemisinin kills Plasmodium that causes malaria

-Metronidazole (Flagyl) interferes with anaerobic bacteris and treats Trichomonas, giardiasis and amebic dysentery

Antihelminthic drugs

-Niclosamide prevents ATP production and treats tapeworms

-Praziquantel alters membrane permeability and treats tapeworms and flukes

-Mebendazole and albendazole interfere with nutrient absorption and treats intestinal helminths

-Ivermectin paralyzes helminths and treats roundworms and mites

Disk-diffusion method (Kirby-Bauer test)

-Tests the effectiveness of chemotherapeutic agents

-Paper disk with a chemotherapeutic agent are placed on agar containing the test organism

**Zone of inhibition around the disk determines the sensitivity of the organism to the antibiotic

Disk-diffusion: Figure

E test

Determines the minimal inhibitory concentration (MIC)

-Lowest abx concentration preventing bacterial growth

E test Figure

Broth Dilution tests

Determine the MIC and minimal bactericidal concentration (MCB) of an antimicrobial drug

Test organism is placed into the wells of a tray containing dilutions of a drug; growth is determined

Antibiograms

Reports that record the susceptibility of organisms encountered clinically

Microdilution plate used for testing the MIC of antibiotics

Persister cells

microbes with genetic characteristics allowing for their survival when exposed to an antibiotic

Superbugs

bacteria that are resistant to large number os antibiotics

Resistance genes are often spread horizontally among bacteria on plasmids or transposons via ________ or _______

conjugation or transduction

Name the 5 mechanisms of resistance

1. Enzymatic destruction or inactivation of the drug

2. Prevention of penetration to the target site within the microbe

3. Alteration of the drug's target site

4. Rapid efflux (ejection) of the antibiotic

5. Variations of mechanisms of resistance

Bacterial Resistance to Antibiotics : Figure20.20

Misuse of antibiotics selected for resistance mutants

Misuse includes:

-using outdate or weakened antibiotics

-using antibiotics for the common cold and other inappropriate conditions

-using antibiotics in animal feed

-failing to complete the prescribed regimen

-using someone else's leftover prescription

Antibiotic Safety

-Therapeutic index: Risk versus benefit

-Reaction of antibiotics with other drugs

-Damage to organs

-Risk to fetus