Lecture 11: Antimicrobial drugs Flashcards
Antimicrobial Drugs are used when?
Used when immunization has not occurred (no successful vaccine) and the immune system has difficulty to eliminate infection (ex: HIV)
• Useful against bacterial infection (antibiotics), very few antivirals (used for viral infection) are available (& those avail. are so restricted/limited)
Antimicrobial Drugs
These are compounds that…kill (cidal/lytic) or control the growth (static) of microorganisms in the host
• These drugs MUST display SELECTIVE TOXICITY or they will cause damage to the host
- b/c an antibiotic not used topically, is being let loose in body (full access to tissues) - ensure it won’t do non-specific tissue damage
What are the Two broad categories of antimicrobial drugs>
SYNTHETIC (mostly failed - b/c have to design drug that has appro. polarity, size characteristics, no natural transporters exist, therefore, challenging & has to get to min. inhibitory [ ] in tissue (bone, or nervous tissue for ex which is diff) AND NATURAL (out #)
• Large number of naturally occurring antibiotics with no clinical use
- (naturally) Produced by bacteria and fungi (penicillium or straphylosporium for ex)
Antimicrobial Drugs
Can also be described based on whether they are:
Bacteriostatic or bacteriocidal
• Broad spectrum or narrow spectrum
- broad could be: target all gram + & gram - (broad over 1 that only targets gram -), BUT can also be broad if target all gram - (vs. 1 that targets just E. coli)
Antibiotic targets include:
Cytoplasmic membrane structure & function
anything that targets cytoplasmic mem, mostly has:
TOXICITY TO US –> NOT AS WIDELY USED
- b/c our PM as Euk cells & their PM as a prok. cell are comparable to 1 another which means not something you can easily target without causing harm to your cell
Cell Wall Active Antimicrobial Drugs
Cell wall active agents offer EXCELLENT SELECTIVE TOXICITY • MOST WIDELY USED class of antibiotics
- no harm to OUR own cell b/c we lack PD, therefore don’t target anything we have apart of our cell
- but can dev. allergy if it complexes with proteins in our blood for ex, behaving like a hapten & manages to get attention of immune system (not common)
The largest class of cell wall active antimicrobial drugs are….
beta lactam antibiotics
Describe the characteristics of beta lactam antibiotics
Common feature is the b-lactam ring
- core for all this category of antibiotic (can be dressed up with diff functional groups –> will determine where drug could go & conseq. for inside of cell & what the targets will be & how will it be given (orally or IV)
• NATURALLY occurring: produced by Penicillium and Cephalosporium fungi
- found as products of microbial metabolism
- each produce diff. categories of B-lactam; *all have ring but dressed up differently
• Example: penicillins and cephalosporins
• Can be MODIFIED in the lab to produce SEMI-SYNTHETIC drugs that have a modified spectrum of activity
- Reason for this: to change spectrum of activity; give it more activity against a gram - or gram +, more activity against a partic. species of bact.
• Susceptible to beta-lactamases
- Enzyme produced by some bugs to cut and inactivate beta-lactams (drug no longer works - good for bact but not for us)
- THEREFORE, B-lactamase is a FORM OF ANTIBIOTIC RESISTANCE
Penicillins
Cell Wall Active Antimicrobial Drug
Penicillins have a NARROW spectrum of activity
- prod. by penicillum mold (natural)
• Characterized by a FIVE membered ring (thiazolidine) attached to the beta-lactam component
*• Target TRANSPEPTIDATION in GRAM POSITIVE bacteria
• CANNOT PENETRATE outer membrane of GRAM NEGATIVE bacteria (don’t work against gram -)
- SEMI-SYNTHETIC penicillin are modified to provide SOME ACTIVITY AGAINST gram NEGATIVE bugs
- Example: ampicillin
*(can’t predict these sorts of things, so have to test antimicrobial in lab to see if these drugs will work against gram +/- experimentally)
Explain Ampicillin
Explain how Penicillins target transpeptidation in gram +’s
transpeptidation: creates perpendicular cross-links using peptide chains
penicillin drug binds to transpeptidase (enzyme respon. for formation of cross-links)
outcome: WEAK CELL WALL
- when H20 rushes into hypertonic envir. of cell, it’ll cause cell to rupture –> bact no longer viable
Not all penicillins will be.
susceptible to B-lactamase enzymes
Cephalosporins
Cell Wall Active Antimicrobial Drugs
• Structurally distinct from penicillins (despite sharing B-lactam ring)
- SIX membered ring is attached to the beta-lactam component
- Also target transpeptidation of peptidoglycan (like penicillin)
- Many semi-synthetic examples (enhance activity & increase spectrum of activity etc.)
- BROADER SPECTRUM of activity than penicillin (cast wider net –> target more than penicillin can target)
- BETTER RESISTANCE against beta lactamases (harder for B-lactamase enzyme to activate & cut same B-lactam ring the penicillum’s had b/c less accessible due to change of chem)
- Grouped into GENERATIONS
- 1st generation cephalosporin, 2nd generation cephalosporin etc.
- each gen. will have its own characteristic target & outcome - what its able to go after (gen categories play role in est. & understanding what the function of category will be)
- all have cepha as route –> cepha - beginning of each antibiotic
- associate ending with what gen it belongs to & will then associate that with which gen will work against gram -‘s better etc. to choose best for situation
Growth Factor Analogs
Growth factor analogs (drugs) are structurally similar to growth factors but do not function (behave) in the cell
• Analogs similar (resemble) to vitamins, amino acids, and other compounds (necessary in process)
Give an example of growth factor analogs
FULL SYNTHETIC category (man-made)
- recently quite lost efficiency –> don’t use them to same degree as before
- even when might be useful, they have a *lot of resistance (organism may have resistance to drug)
• Discovered by Gerhard Domagk in the 1930s
- Example: sulfanilamide
• Inhibit growth of bacteria by INHIBITING FOLIC ACID SYNTHESIS and thus NUCLEIC ACID SYNTHESIS
- needed for syn of nitrogenous bases; to be able to assemble in bact cell, things like purines & pyrimides & also in biosyn. of some AA’s as well
- BACT has a biosyn pathway that does this - BUT for humans we get folic acid from our diet to satisfy req’s, therefore safe for us (no issue with toxicity b/c of that –> PERFECT SELECTIVE TOXICITY)
• Often used in COMBINATION with another analog –> TRIMETHOPRIM
- Combination therapy MINIMIZES the LIKELIHOOD of RESISTANCE
Isoniazid
Growth Factor Analogs
• Extremely narrow spectrum cell wall active agent
• Analog of mycolic acid component needed by Mycobacterium spp.
Quinolones
Nucleic Acid Synthesis Inhibitors
Synthetic antimicrobials
- Inhibit DNA gyrase; prokaryotic enzyme; we don’t have it so good selective toxicity
- Prevents supercoiling of DNA
• Active against both Gram-negative and Gram-positive bacteria
Provide an ex of Quinolones
- Example: ciprofloxacin a fluorinated quinolone (fluoroquinolone)
- Useful against life threatening infections
- complex chest infection, uti thats complicated
What is the problem with ciprofloxacin
it interferes with cartilage development; if women is pregnant can’t give them this b/c entire fetal skeleton is 1st cartilage then forms into bone
• Rifampin:
Nucleic Acid Synthesis Inhibitors
: binds to RNA polymerase preventing transcription
• Actinomycin
: Binds to DNA template blocking transcription elongation
Protein Synthesis Inhibitors
• Protein synthesis inhibitors target 70S ribosomes; inhibit translation
• Good selective toxicity
• Some issues because human cells have 70S ribosomes in the mitochondrial
matrix
Aminoglycosides
Protein Synthesis Inhibitors
- Bind to the 30S subunit of 70S ribosomes
- Block translation
- Narrow spectrum
- Useful against gram negative bugs
- Often used as a last resort drug
- Damaging to the kidneys and ears
• Examples include streptomycin,
gentamycin and neomycin
Tetracycline
Protein Synthesis Inhibitors
• Broad spectrum
• Produced by species of the Streptomyces genus
• Bind to the 30S subunit
• Consist of both natural and modified semisynthetic
drugs
• Binds to calcium damaging teeth and bone
• Shouldn’t be used in children and pregnant
women
• Used in veterinary medicine and to promote
animal growth
• Creates problems with resistance
• Macrolides
• Broad spectrum of activity
- Bind to the 50S ribosomal subunit
- Only inhibits translation of some proteins
- Some proteins are preferential translated and others are not
- Creates a detrimental protein imbalance inside of the cell
- Useful to treat infection in patients with allergies to beta lactam antibiotics
- Example: erythromycin and azithromycin
- Produced by Streptomyces spp.
Daptomycin
• Produced by Streptomyces spp.
• Cyclic lipopeptide
• Active against Gram-positives
• Pathogenic Staphylococcal spp. and
Streptococcal spp.
• Forms pores in the plasma membrane causing
depolarization
• Cell cannot synthesize necessary biomolecules
• Cell death occurs
• Resistance can occur when bacteria alter plasma
membrane composition
Platensimycin
- Inhibits fatty acid biosynthesis
- Produced by Streptomyces platensis
- Broad spectrum of activity against gram positive bacteria
- Useful against important resistant gram positive pathogens
- MRSA and VRE
- Does not cause toxicity in the host
Antibiotic Resistance
Antibiotic resistance occurs when an organism develops a mechanism
to elude the activity of an antimicrobial drug that it should otherwise
be susceptible to
• Genes for antibiotic resistance can either be encoded on a plasmid or directly
within the genome
Describe
Reduced permeability Penicillins
Inactivation of antibiotic Penicillins, chloramphenicol, aminoglycosides
Alternation of target Erythromycin, streptomycin, norfloxacin
Development of resistant biochemical pathway Sulfonamides
Efflux- multi drug resistance
