Lecture 3, Antibiotics I Flashcards
Old definition of antibiotics and some examples
A compound produced by an organism that is antimicrobial. ex. Penicillin, Aminoglycosides-Streptomycin, Chloramphenicol,
Old definition of chemotherapeutic agent and some examples
Synthetically produced compound that is antimicrobial ex. Sulphonamides, Quinolones, Salvarsan
Beta-Lactam antibiotics. What are the multiple classes of beta-lactams? Mechanism? Used against?
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.
What are the beta-lactamase inhibitor drugs called?
Clavulanic acid
Sulbactam
Tazobactam
What are the mechanisms of beta-lactam antibiotic resistance?
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
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?
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-
What is Metallo Beta-Lactamase, MBL?
Bact enzyme that hydrolyzes Carbapenems. Usually in ghram negatives
What does MRSA stand for? What is it resistant to? What is used to treat it?
Methicillin Resistant Staph Aurteus, a Gram positive bacteria
Resistant to all beta lactamse and beta lactamase inhibitors
Treatments: - Vancomycin - Quinupristin-Dalfopristin - Mupirocin - Sulfonamides + Trimethoprim
Glycopeptide antibiotics, Two drugs: Mechanism: Targets: Some Resistant bacteria
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.
Polypetide antibiotics two drugs: structure: mechanism: targets: side effects and usage:
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.
Antibiotics that target the 50S subunit of bacterial ribosomes?
Macrolides - (Erythromycin)
Lincosamides
Chloramphenicol
Linezolid - (Oxaloidinones)
Streptogramins
What are the subuints of prokaryotic ribosomes? Eukaryotic?
Prokaryotes: 50S, 30S Eukaryotes: 60S, 40S
Macrolides Some names:
Mechanism Targets
Side effects and
toxicity
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.
Lincosamides
Mechanism
Names
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.
Linezolid
Mechanism and targets
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.
Quinupristin-Dalfopristin
Mechanism
Targets
Inhibits the peptidyltransferase activity of the 50S subunit
Bactericidal
Against Gram positive cocci, MRSA
Aminoglycosides
Names
Mechanism
Targets
Types of resistant bacteria
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.
Mupirocin
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
Sulfonamides
Mechanims
Targets
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)
Trimethoprim
Mechanism
Targets
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
Side effects and toxicities of Sulfamethoxide and trimethoprim,
the ratio of the two in use
Resistances that can develope
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.
3 Antibiotics that inhibit DNA synthesis (directly)
Fluroquinolones and quinolones
Metronidazole
Rifampin
Quinolones
Name
Mechanim
Uses
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.
Fluoroquinolones
Drug names
Mechanism
Uses
Resistances that can be acquired
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.
Metronidazole
What class of drugs is it in?
Mechanism
Targets
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)
Rifampin
Mechanism
Targets
Binds bacterial RNA polymerase
Good vs. Gram Positive Cocci
Bactericidal vs. Mycobacterium
Used to treat and prevent Meningococcus
Nystatin
Narrow spectrum antifungal
Binds membrane sterols and disentigrates plasma membrane
Polymyxin
Binds membrane phospholipids
inhibits membrane transport
bactericidal
vs. Gram negative
Daptomycin
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.
What are the 5 classes of beta lactams?
Penicillins Cephalosporins Carbapenems Monobactams
5th class is the beta-lactamase inhibitors: Clavulanic Acid, Sulbactam, Tazobactam.
What beta lactam type antibiotics are hydrozyed by Metallo-beta-lactamase?
Carbapenems
What antibiotics are hydrolyzed by the extended spectrum beta lactamase?
Penicillins and Cephalosporins.
