Lecture 3, Antibiotics I

Question 1

Old definition of antibiotics and some examples

Answer 1

A compound produced by an organism that is antimicrobial. ex. Penicillin, Aminoglycosides-Streptomycin, Chloramphenicol,

Question 2

Old definition of chemotherapeutic agent and some examples

Answer 2

Synthetically produced compound that is antimicrobial ex. Sulphonamides, Quinolones, Salvarsan

Question 3

Beta-Lactam antibiotics. What are the multiple classes of beta-lactams? Mechanism? Used against?

Answer 3

Inhibits the Transpeptidase enzyme that links the amino portion of the cell wall glycoproteins. Most effective against Gram-Positives, some action against Gram-Negatives Bacteriostatic.

the 4 classes: Penicillins Cephalosporins Carbapenems Monobactams “5th” class is the beta-lactamase inhibitors.

Question 4

What are the beta-lactamase inhibitor drugs called?

Answer 4

Clavulanic acid

Sulbactam

Tazobactam

Question 5

What are the mechanisms of beta-lactam antibiotic resistance?

Answer 5

1) Expression of Beta-Lactamase enzyme - secreted by G+ and stored in the periplasm of G-
2) Elevated expression of transpeptidase and other cell wall synthetic enzymes
3) Mutated Proptein Binding Proteins (ie mutated transpeptidase, as seen in MRSA)
4) Altered porin expression, Excluding Beta-lactams from passing the outer cell membrane in G-s

Question 6

What is Extended Spectrum Beta-Lactamase, ESBL? What drugs can counteract them? What drugs are not affected by them? Are they usually in gram positives or negatives?

Answer 6

The bacterial enzyme which hydrolyzes Penicillins and Cephalosporins.

Beta-lactamase inhibitors Clavulanic acid, sulbactam, and tazobactam are effective against them.

Carbapenems and Monobactams are effective still.

Usually in G-

Question 7

What is Metallo Beta-Lactamase, MBL?

Answer 7

Bact enzyme that hydrolyzes Carbapenems. Usually in ghram negatives

Question 8

What does MRSA stand for? What is it resistant to? What is used to treat it?

Answer 8

Methicillin Resistant Staph Aurteus, a Gram positive bacteria

Resistant to all beta lactamse and beta lactamase inhibitors

Treatments: - Vancomycin - Quinupristin-Dalfopristin - Mupirocin - Sulfonamides + Trimethoprim

Question 9

Glycopeptide antibiotics, Two drugs: Mechanism: Targets: Some Resistant bacteria

Answer 9

Vancomycin, Teicoplanin

Bind to the Ala-Ala portion of the Gram + peptidoglycans, blocking the binding site for transpeptidase enzyme.

Bacteriostatic

Only effective against Gram-positives, does not pass Gram neg cell outer membrane.

Vancomycin Resistant Enterococcus (VRE) Has Ala-Lactate instead of Ala-Ala. ablating the vancomycin binding syte.

Question 10

Polypetide antibiotics two drugs: structure: mechanism: targets: side effects and usage:

Answer 10

Colistin,

Polymyxin B

Amphipathic polypeptides that insert into the membrane, destablizing it like a detergent, causing disentigration and cell lysis, bactericidal

Only works against Gram negatives, where it can reach the outer cell membrane: Acinetobacter, Ps. aeruginosa, Stenotrophomonas.

Side effects: Significant kidney toxicity Destruction of GI flora, along with poor absorption. Neurotoxicity, vertigo, visual impairments, confusion

Not for oral use, used in eye drops, wound salves, and I.V. injection.

Question 11

Antibiotics that target the 50S subunit of bacterial ribosomes?

Answer 11

Macrolides - (Erythromycin)

Lincosamides

Chloramphenicol

Linezolid - (Oxaloidinones)

Streptogramins

Question 12

What are the subuints of prokaryotic ribosomes? Eukaryotic?

Answer 12

Prokaryotes: 50S, 30S Eukaryotes: 60S, 40S

Question 13

Macrolides Some names:

Mechanism Targets

Side effects and

toxicity

Answer 13

One of the two “mycins” Erythromycin, CLarithromycin, Azithromycin, Biaxin

Bind 50S bacterial subunit and prevent mRNA movement through the subunit as well as tRNA attachment to the ribosome.

Bacteriostatic.

Broad spectrum against Gram Positives

Also good against atypical bacteria: Legionella, Mycoplasma, Chlamydia

Alone has mild side effects, GI irritation

Is contraindicated for use along with statins, causes myopathy and long QT.

Question 14

Lincosamides

Mechanism

Names

Answer 14

The seond “mycins”

Lincomycin, clindamycin, pirlimycin

Binds to the 50S subunit and causes premature dissociation of the peptidyl tRNA molecule.

Same targets and effects as the macrolides.

broad spectrum against G+, and good against atypicals

mild GI side effects, with strong myopathy and long QTs when coupled with statins.

Question 15

Linezolid

Mechanism and targets

Answer 15

An antibiotic that inhibits the 70S translation initiation complex formation.

Inhibits N-f-Methionine binding.

Effective against most gram positives

Uused for the treatment of serious infections caused by Gram-positive bacteria that are resistant to other antibiotics, such as VRE (vancomycin Resistant Enterococcus) and MRSA.

Question 16

Quinupristin-Dalfopristin

Mechanism

Targets

Answer 16

Inhibits the peptidyltransferase activity of the 50S subunit

Bactericidal

Against Gram positive cocci, MRSA

Question 17

Aminoglycosides

Names

Mechanism

Targets

Types of resistant bacteria

Answer 17

Streptomycin, Gentamycin, Netilmycin,

Neomycin–> only used in eyedrops

Bind 30S subuint and inhibit aminoacyl-tRNA binding. Bacteriostatic

Requires O2 to be transported in. only effective against aerobic bacteria.

Used in combination with cell wall synthesis inhibitors for endocarditis.

Highly resistant microbes have 30S ribosome mutation.

Weakly resistant microbes utilize more anaerobic metabolism.

Question 18

Mupirocin

Answer 18

Binds to 30S subunit, prevents specifically isoleucine-tRNA binding

Narrow spectrum specifically vs. Staphylococci and Streptococci (G+)

Locally effective vs. MRSA and impetigo

made by the microbe Pseudomonas fluorescens

Question 19

Sulfonamides

Mechanims

Targets

Answer 19

Inhibits the enzyme Dihyropterate Synthase

Prevents Dihydropterate formation, preventing Dihydrofolate formation

preventing Tetrahydrofolate formation

TH4

Inhibiting DNA, RNA, synthesis, as well as SAM synthesis, which inhibitys methionine and cysteine synthesis.

Sulfonamides + Trimethoprim

Broad spectrum against both gram positive and negatives,

good vs.

MRSA,

Pneumocystis Pneumonia

Stenotrophomonas maltophila

Nocardia

Enteric G- rods

Allergies to Sulfonamides are common (~3%, like penicillin)

Question 20

Trimethoprim

Mechanism

Targets

Answer 20

Inhibits the enzyme dihydrofolate reductase

Inhibitin TH4 produciton, disruptin DNA, RNA, and amino acid synthesis

Sulfonamides + Trimethoprim

Broad spectrum vs. G+ and G-, MRSA, Pneumocystis Pneumonia, Stenotrophomonas maltophila, Nocardia, Enteric G- rods

Question 21

Side effects and toxicities of Sulfamethoxide and trimethoprim,

the ratio of the two in use

Resistances that can develope

Answer 21

5:1 Sulphamethoxide:Trimethoprim

Potential very severe toxicities

1) Rash taht can progress to lethal SJS and toxic epidermal necrosis
2) thrombocytopenia
3) Leukocytopenia
4) hepatitis
5) hyperkalemia

Resistances involve mutation to the dihydropterate synthetase enzyme, extending cross resistance to all sulfonamides.

Question 22

3 Antibiotics that inhibit DNA synthesis (directly)

Answer 22

Fluroquinolones and quinolones

Metronidazole

Rifampin

Question 23

Quinolones

Name

Mechanim

Uses

Answer 23

Norfloxacin aka Nalidixic Acid

Inhibits bacterial Topoisomerase II (DNA gyrase) and Topoisomerase IV

Cleaves DNA after binding Topoisomerase, causing bactericidal effect.

Used primarily for UTIs, because they are highly bound by proteins, plasma proteins, limiting their systemic availability.

Question 24

Fluoroquinolones

Drug names

Mechanism

Uses

Resistances that can be acquired

Answer 24

Ciprofloxacin, Ofloxacin, Levolfloxacin,

Moxifloxacin

Same mechanism as quinolones, binds topisomerase II and IV, cleaves DNA, bactericidal

Difference is that fluoroquinolones have low protein binding, and thus can be used systemically. Do not penetrate into CSF though.

Resistance is qcuired only if both of the Topoisomerase target enzymes are altered.

Question 25

Metronidazole

What class of drugs is it in?

Mechanism

Targets

Answer 25

Nitroimidazole class

Diffuses into cells and in anaerobic metabolic processes it is reduced, producing reactive intermediates which damage the microbe DNA, RNA, proteins, lipids, etc.

Good vs. Anaerobic bacteria, Microaerophilic bacteria, and Protozoans.

Resistances are very rare, requiring changes or decreases in the redox reactions that activate the drug.

inhibits pyruvate oxidase, dehydrogenase, acetyl-coa synthesis (ask lab teacher to clarify)

Question 26

Rifampin

Mechanism

Targets

Answer 26

Binds bacterial RNA polymerase

Good vs. Gram Positive Cocci

Bactericidal vs. Mycobacterium

Used to treat and prevent Meningococcus

Question 27

Nystatin

Answer 27

Narrow spectrum antifungal

Binds membrane sterols and disentigrates plasma membrane

Question 28

Polymyxin

Answer 28

Binds membrane phospholipids

inhibits membrane transport

bactericidal

vs. Gram negative

Question 29

Daptomycin

Answer 29

Used against VRE and Staphylococcus

Binds Ca++ and forms oligomeric micelles

These micelles deliver the drug into gram positive bacteria (can’t pass through the outer membrane of G-neg, idk maybe it gets stuck in it or something)

Causes leakage/lysis of cell membrane.

Question 30

What are the 5 classes of beta lactams?

Answer 30

Penicillins Cephalosporins Carbapenems Monobactams

5th class is the beta-lactamase inhibitors: Clavulanic Acid, Sulbactam, Tazobactam.

Question 31

What beta lactam type antibiotics are hydrozyed by Metallo-beta-lactamase?

Answer 31

Carbapenems

Question 32

What antibiotics are hydrolyzed by the extended spectrum beta lactamase?

Answer 32

Penicillins and Cephalosporins.