Antimicrobial Drugs & Resistance

Chemotherapeutic agents

Chemicals that fight against diseases in humans and animals

Immunotherapeutics

Involves treating diseases by inducing, enhancing, or suppressing the immune response, such as through the use of antibiotics

3 general principles of antimicrobial therapy

(1) drug must have selective toxicity for target microbe, (2) drug has to be able to reach the target at the right concentration, (3) once the drug reaches the target cell, it must be able to bind to and penetrate the cell (avoiding inactivation and extrusion)

Therapeutic index

(toxic dose)/(therapeutic dose)

A… therapeutic index is favorable

High

Negative consequence of broad-spectrum drugs

They may disrupt the natural population of bacteria in the body

Cidal agents

Kill microbes

Static agents

Inhibit microbes’ growth

Superinfection

Overgrowth of the normal microbiota that is resistant to antibiotics

Minimum inhibitory concentration (MIC)

The lowest concentration of a drug that is effective in inhibiting the growth of the pathogen

What can be used to approximate the MIC?

Etest, which uses strips that contain a gradient of the antibiotic; or serial dilution

Antibiotics were discovered by…

Alexander Fleming; they kill or neutralize bacteria

Antibiotics are produced by…

Bacteria and fungi; as a natural defense mechanism against other bacteria

Genus of bacteria that produces antibiotics

Bacillus

Genus of fungi that produces antibiotics

Penicillium

Antibiotics are… meaning they are…

Secondary metabolites; not usually produced, but some kind of environmental change may induce their production

Kirby-Bauer method

Used to determine a microbe’s susceptibility to an antimicrobial agent

Zone of inhibition

Produced around antimicrobial disk; diameter can be quantified and compared against existing tables to determine whether the drug will be sufficiently effective in the body

5 mechanisms of action for antimicrobial drugs

(1) cell wall synthesis inhibitors, (2) protein synthesis inhibitors, (3) metabolic antagonists, (4) nucleic acid synthesis inhibitors, (5) inhibitors of cell membrane function

Most important target for antibiotics

Cell wall

How do antimicrobial drugs inhibit protein synthesis?

They target ribosomes

What mechanisms of antimicrobial drugs are the most successful?

cell wall synthesis, protein synthesis, and metabolic process inhibitors (because these processes are different between pros and euks)

Significance of ribosome differences between prokaryotes and eukaryotes

Antibiotics harm bacteria and not human cells

Penicillins

Antibiotics that inhibit the final step in bacterial cell wall synthesis, peptidoglycan synthesis (transpeptidation), causing the cell to lyse

b-lactam ring

Common feature of all penicillins; made of three C atoms and one N atom

b-lactamase/penicillinase

Enzyme that destroys the b-lactam ring of penicillins; confers resistance to penicillin

The b-lactam ring binds to…

Specialized proteins on the bacterial cells

Semisynthetic penicillin

Chemically modified natural penicillin; has a broader range than natural penicillin

Penicillin G

Natural penicillin particularly effective against gram+ bacteria; most effective natural form of penicillin

Methicillin

Semisynthetic; resistant to penicillinase, but less effective than penicillin G; used to fight Staph infections

MRSA

Strain of Staph resistant to methicillin

Cephalosporins

Antibiotics functionally and structurally similar to penicillin; have b-lactam rings; prescribed to patients allergic to penicillin

Vancomycin

Glycopeptide antibiotic that blocks transpeptidation during cell wall synthesis; inhibits cell wall synthesis at a different point than penicillin and cephalosporin; NO b-lactam ring

Vancomycin is effective against…

MRSA; “drug of last resort”

When is vancomycin perscribed?

When absolutely necessary

Teixobactin

New antibiotic that kills some gram+ bacteria

Isoniazid

Inhibits the synthesis of mycolic acid in mycobacteria

Many antibiotics work by specifically binding to the… subunits of prokaryotic ribosomes

small (30s) and large (50s)

Aminoglycoside antibiotics

Bind to small (30s) ribosomal subunit, disrupting process of correctly reading the mRNA

Example of aminoglycoside antibiotics

Streptomycin and gentamicin

Common problems with aminoglycoside antibiotics

Resistance and toxicity

Tetracyclines

4-ring structure with many side chains attached; bind and combine with the small (30s) ribosomal subunit, preventing aminoacyl-tRNA molecules from binding to A site

Tetracyclines are (broad-/narrow-spectrum) and (bacteriostatic/cidal)

Broad-spectrum; bacteriostatic

Tetracyclines are often prescribed to treat…

Acne

Macrolide antibiotics

Several (12 to 22) C lactone rings linked to sugars; binds to 23s rRNA of large (50s) subunit, inhibiting elongation

Erythromycin

Macrolide antibiotic that affects protein synthesis

Macrolide antibiotics are commonly prescribed for…

Patients allergic to penicillin

Chloramphenicol

Only used in life-threatening situations because its extremely toxic; similar to erythromycin/macrolides in mode of action (blocks elongation); chemically synthesized

A common pathway targeted by antibiotic antimetabolites is… because…

Folic acid synthesis; humans are not able to synthesize folic acid

Sulfonamides and trimethoprim…

Disrupt the folic acid synthesis pathway

Sulfonamides

Block folic acid synthesis by acting as analog of PABA, a precursor in the pathway

Trimethoprim

Synthetic; acts as a competitive inhibitor of DHFR (later in the pathway than sulfonamides)

Synergistic effect

Additive effect; when trimethoprim and sulfonamides are prescribed together in Septra

Augmentin

Synergy; combination of amoxicillin and b-lactamase inhibitor

Isoniazid and rifampin

Synergy; isoniazid inhibits cell wall synthesis and rifampin inhibits nucleic acids; treat TB

Antagonism

When two drugs are less effective when used together than when used alone; penicillin and tetracyclines

How are antibiotics that inhibit nucleic acid synthesis made selective against prokaryotes?

Targeting enzymes involved in the process of prokaryotic DNA replication or transcription

Quinolones

Broad-spectrum and synthetic; inhibit DNA gyrase and DNA topoisomerase, which are involved in making the DNA supercoiled

Ciprofloxacin (Cipro)

Quinolone; disrupts DNA replication

Rifampicin

Drug that is part of the common treatment for TB; inhibits RNA polymerase

Polymyxin B

Inhibitor of cell membrane function; binds to plasma membrane, disrupting its structure and permeability; extremely toxic to the kidneys in particular

Why is horizontal gene transfer of antibiotic resistance genes problematic?

Because a particular kind of resistance can apply to multiple classes of drugs

The spread of antibiotic-resistant bacteria is due to…

Selective pressures and genetic factors

Selective pressures

Natural selection favors bacteria with antibiotic resistance because they are more likely to survive and reproduce than bacteria without resistance

Genetic factors

Once antibiotic resistance has evolved through spontaneous mutation, it can be spread to strains through horizontal gene transfer

5 mechanisms of drug resistance

(1) preventing entrance of the drug, (2) using efflux pumps to remove the drug before it can have an effect, (3) inactivating the drug, (4) modifying the enzyme or organelle that the drug targets, (5) using an alternative pathway or increasing production of a target molecule

In bacteria, resistance genes can be found in…

Bacterial chromosomes, plasmids, and transposons

Bacterial chromosomes

Where spontaneous mutations that convey antibiotic resistance usually occur

Resistance (R) plasmids

Plasmids with multiple antibiotic resistance genes; can be transferred with the plasmid via conjugation, transduction, or transformation

Transposons

“Jumping genes;” mobile gene elements that can jump from the bacterial chromosome to a plasmid and back to the chromosome; composite transposons carry resistance gene

Humans can prevent drug resistance by…

Prescribing antibiotics in high enough concentrations and in the correct combinations to kill all of the bacteria; doctors can prescribe fewer antibiotics; researchers can develop new drugs and treatments

Why is it easier to achieve selective toxicity with antibiotics than with antifungal drugs?

Because fungi are eukaryotes

Since most viral infections are incurable, many antiviral drugs simply…

Limit the duration or severity of the illness

Drugs that fight HIV target…

HIV RT and HIV protease

HIV RT converts ssRNA to…

dsDNA

HIV protease

Enzyme that cuts proteins during post-translational modification

Why are protease inhibitors powerful antivirals?

They inhibit post-translational modification of viral proteins

Tamiflu

Antiviral; neuraminidase inhibitor; inhibits influenza virus

Acyclovir

Antiviral; prevents herpes virus from replicating and is also used to treat shingles; structural analog of guanine

There have been major breakthroughs in the fight against…

Hepatitis C, the leading cause of liver transplants

What is the target of most antifungal drugs?

Ergosterol; unique compound that acts like cholesterol in fungal cell membranes

Azoles

Antifungal; block biosynthesis of ergosterol

Triazole is used to treat… , while imidazoles are used to treat…

systemic fungal infections; cutaneous mycoses

Polyenes

Antifungal; causes leakage of cellular components when they bind to sterols in cell membrane (e.g. amphotericin B)

Griseofulvin

Antifungal; naturally produced by Penicillium fungi; used to fight superficial fungi; inhibits microtubule formation

Chloroquine

Anti-parasite drug used to prevent a malarial infection

Metronidazole

Treats infections by a group of anaerobic parasitic protozoans and STIs