MI04 - Antibiotics and resistance

Principles of antibiotics - Selective toxicity

Greater harm to microbes than to humans and other animal hosts

Principles of antibiotics - Therapeutic index

Ratio of lowest dose toxic to host to dose required to kill microorganism

Bacterial Peptidoglycan

is unique to bacteria and a good site of action

Ribosomes of bacteria

are different than animal cells, also a good site of action

Broad spectrum antibiotics

Affects different types of bacteria. Ex: Gram positive, Gram negative

Narrow spectrum antibiotics

Affects only a few related types of bacteria

Bacteriostatic

-static means inhibits growth

Bactericidal

-cidal means kills

Adverse effects

Allergic reactions. Common with penicillin, start with one antibiotic, if allergic, try another.

Adverse effects

Reduction of normal microbiota. C. diff, antibiotic associated colitis.

Antibiotics are usually first created by

some natural organism.

Newer generations of antibiotics use BLANK to improve antibiotics

chemical modifications

Moenomycin

A peptidoglycan transglycosylation inhibitor

What does an assay of antibiotics do?

Measures effectiveness through Minimum inhibitory concentration (MIC) and Minimum lethal concentration (MLC)

Minimum inhibitory concentration

The minimum concentration of an antimicrobial agent that stops visible growth of a microorganism after overnight incubation

Minimum Lethal Concentration

the lowest concentration of an antimicrobial agent needed to kill 99.9% of a specific bacterial or fungal population after a set incubation period

Zone of inhibition

Where the concentration is strong enough to stop growth, a clear ring appears. Where the drug becomes too weak, microbes resume growing

Dilution Assay

Helps to determine MIC.

Penicillins importance

First antibiotic, affects the cell wall, WAS extremely effective.

Penicillins mechanism

Prevents synthesis of cell wall by blocking cross linking of peptidoglycan

Resistance to penicillins mechanism

Due to beta-lactamases that CLEAVE the antibiotic. Penicillinases

What does penicillin activity depend on?

The beta-lactam ring, which is cleaved by beta lactamases

What can overcome beta-lactamases?

Augmentin, or a Beta lactamase inhibitor

What is methicillin?

A beta lactam antibiotic resistant to penicillinases. Bacteria ended up developing methicillinases, BUT MECHANISM IS STILL CELL WALL

What are cephalosporins?

Cephalosporins are also beta lactam antibiotics resistant to penicillinases. Can also have cephalosporinases, MECHANISM IS STILL CELL WALL

What are carbapenems?

MECHANISM IS STILL CELL WALL SYNTHESIS, but has activity against gram negative and gram positive.

BOTH anti peptidoglycan synthesis activity and beta lactamase inhibitor activity

What kind of resistance has emerged to carbapenems?

Efflux pumps, new beta lactamases, modified porins in gram negative bacteria, modified penicillin binding proteins.

What are tetracyclines?

Inhibitors of protein synthesis, Ex: doxycycline

What is chloramphenicol?

A last resort antibiotic that has bad side effects. Good for meningitis, but causes patient death aplastic anemia.

What is chloramphenicol’s mechanism?

It is a bacteriostatic, stopping cell growth through stopping protein synthesis

What do aminoglycosides do?

Inhibit protein synthesis, affecting ribosome function.

What are some examples of aminoglycosides?

Streptomycin, gentamycin, erythromycin, and clindamycin.

What classification does erythromycin fall under?

a macrolide

What classification does clindamycin fall under?

A lincosamide.

What are polypeptide antibiotics?

Antibiotics that insert into/disrupts bacterial membranes.

Examples of polypeptide antibiotics?

Polymyxin B, Bacitracin

What is rifampin?

An antibiotic that binds to RNA polymerase and inhibits mRNA synthesis

Antibiotics that inhibit DNA replication?

Nalidixic acid, Fluoroquinolones (Ciprofloxacin), and novobiocin.

What does Nalidixic acid, Fluoroquinolones (Ciprofloxacin), and novobiocin target?

DNA Gyrase

Antibiotics specific for anaerobes?

Metronidazole, disrupting ETC leading to DNA damage. It must be activated by these anaerobic organisms.

What antibiotic inhibits folic acid synthesis?

Trimethoprim. Often delivered as part of formulation called Bactrim

Mode of action antibacterial medication 1:

Inhibition of cell wall synthesis. Cell will grow and lyse.

Mode of action antibacterial medication 2:

Inhibition of protein synthesis. Bacterial growth requires protein synthesis

Mode of action antibacterial medication 3:

Disruption of cytoplasmic membranes. Allows material to leak out cell.

Mode of action antibacterial medication 4:

Inhibition of nucleic acid synthesis. RNA and DNA synthesis required for bacterial growth

Mode of action antibacterial medication 5:

Competitive inhibition. Prevents action of an essential enzyme by competing for active site.

Examples of antibiotic eye drops?

Erythromycin, gentamycin, tobramycin, ciprofloxacin. Erythromycin ointment can also be applied

What limits antimicrobial agents?

Selection of antibiotic-resistant bacteria. Mutations and gene transfer in R plasmids are causes

Issue with antimicrobial hand soaps?

Can lead to disinfectant resistant cells, triclosan

Driver of antimicrobial resistance?

Antibiotics given to farm animals, leads to environmental spread

Antibiotic resistance mechanism 1:

Impermeability - change impermeability so antibiotic does not enter cells. Cannot reach site of action.

Antibiotic resistance mechanism 2:

Binding site altered - change in target so sensitive target site is no longer bound by antibiotic

Antibiotic resistance mechanism 3:

Alternative pathway - developing alternative pathway to bypass inhibited reaction

Antibiotic resistance mechanism 4:

Inactivation of antibiotic - new enzyme appearance inactivating antibiotic. Ex: beta-lactamase.

Antibiotic resistance mechanism 5:

Increase in amount of sensitive site in cell - make too much target for antibiotic in activate

Antibiotic resistance mechanism 6:

Production of a system to excrete the antibiotic Ex: efflux pumps

S. aureus drug resistance patterns

Less than 10-20% of hospital strains are sensitive to penicillin. Beta lactamase and Penicillinase are responsible for this.

What caused methicillin resistance?

Variant of bacterial penicillin binding protein PBP2a, enzymes that crosslink peptidoglycan.