Med Chem - B lactamase inhibitors + Carbapenems + Monobactams Flashcards
name 4 combination products that contain a beta lactamase inhibitor
augmentin
unasyn
sulperazone
sultamicillin
augmentin
amoxicillin + clavulanic acid
sulperazone
cefoperazone + sulbactam
sultamicillin
ampicillin + sulbactam
(another brand for unasyn)
Unasyn
ampicillin + sulbactam
(another brand for sultamicillin)
name 5 beta lactamase inhibitors
which 2 do NOT structurally mimic beta lactam antibiotics
clavulanic acid
sulbactam
tazobactam
avibactam
valorbactam
avibactam and valorbactam do not structurally mimic beta lactam
which beta lactamase inhibitor contains boron
valorbactam
in general, which are more resistant to beta lactamases – penicillins or cephalosporins?
cephalosporins, especially higher generations (3rd) have built in resistance
true or false
beta lactamase inhibitors target PBP
false
THEY HAVE NO ANTIBACTERIAL PROPERTIES
what was the natural starting point with carbapenems and what were the issues with it
thienamycin
had chemical and enzymativ instability
chemical instability in the side chain. terminal NH3+ is electron withdrawing, causing the beta carbon to sulfur to be e- deficient and electrophilic. this will cause sulfur to attack the beta carbon and the reaction will occur because NH3+ is a good leaving group. side chain spontaneously falls apart
enzymatic instability because the beta lactam ring is hydrolyzed by a human renal enzyme called DHP1
imipenam
chemical instability of thienamycin was fixed by adding a terminal atom.
however, enzymatic instability still there
to fix, was combined with CILASTATIN which protects imipenem from hydrolysis
THIS COMBINATION PRODUCT OF IMIPENEM + CILASTATIN IS CALLED PRIMAXIN
meropenem
fixed both issues of thienamycin
no chemical instability because while sulfur and N are still 2 atoms apart, the N is part of a cyclic ring for addtional protection
no enzymatic instability because a METHYL GROUP was added onto the 5 membered ring, providing DHP-1 resistance
what can meropenem be combined with and what is the brand name of this combination product
meropenem + vaborbactam
called VABOMERE
vaborbactam is a non beta lactam, boron containing beta lactamase inhibitor.it enhances the action of meropenem by protecting it from certain serine B-lactamases like klebsiella pneumoniae carbapenemase
true or false
vaborbactam does not have any antibacterial activity
TRUE
the vaborbactam component of vabomere is a ________ ________ inhibitor that protects meropenem from degredation
non-suicidal beta lactamase inhibitor
what was the 1st successful carbapenem that fixed both issues of thienamycin (chemical and enzymatic instability
meropenem
name 4 carbapenems
what was natural prototype
natural prototype = thienamycin
meropenem
imipenem
etrapenem
doripenem
which has more hydrophilic substituents and which has more lipophilic substituents between doripenem and etrapenem
etrapenem has more lipophilic
doripenem has more hydrophilic
structurally, what are monobactams
monocyclic beta lactams
1 and only example of a monobactam
aztreonam
how are monobactams able to have sufficient beta lactam activity, without the beta lactam ring being fused with another ring?
the sulfate substituent (SO3-) gives the structure necessary beta lactam activation
quinolones are bactericidal or static??
explain
rapidly bactericidal
bc they inhibit DNA gyrase (topoisomerase II) and topoisomerase 4 which are key enzymes for dictating the conformation of DNA
why do we say fluoroquinolones have a unique mechanism of action
their target is inside the bacteria
explain the progressive discovery of fluoroquinolones
started with nalidixic acid (not a true quinolone)
structurally modified to oxolinic acid – a true quinolone, but still not good enough
NORFLOXACIN was created, which is considered the prototype for 2nd gen quinolones (aka fluoroquinolones) has a fluorine at the 6 position which is a universal characteristic of 2nd gen quinolones (fluoroquinolones)
name 3 macrolides
erythromycin
azithromycin
clarithromycin
explain the chemical structure of macrolides
large (14-15 membered) lactone ring with a glycosidically linked amino sugar
MOA of macrolides
protein synthesis inhibitor
by binding to 50s ribosomal subunit
bacteriostatic
3 SAR components for macrolides
what was the prototype?
prototype was erythromycin
decosamine
cladinose
lactone (ester linkage in cyclic form)
name a ketolide
telithromycin
which has a lower incidence of developing resistance and why - macrolides or ketolides?
ketolides because of the switch from 3-cladinose to 3-ketone in ketolides
thus, methylase gene expression of bacteria does NOT induce resistance
true or false
telithromycin is for oral administration
true
MOA of ketolides
same as macrolides
inhibit protein synthesis by binding 50s ribosomal subunit
explain the characteristics of fidaxomicin
macrocyclic, but NOT a macrolide because there has to be a cyclic ester and amino sugar but fidaxomicin does NOT have an amino sugar
extremely narrow spectrum and administered orally for c diff infection
MOA fidaxomicin
inhibits bacterial RNA polymerase
SELECTIVELY eradicates c diff with minimal dectruction to healthy flora
fidaxomicin is _____ derived
NATURALLY
fidaxomixin is part of a new class of ______ spectrum ____ antibiotics
narrow spectrum macrocyclic antibiotics
(but NOT a macrolide - no amino sugar)
bezlotoxumab
human monoclonal antibody designed to prevent the recurrence of c diff infection
name 2 lincosamides
lincomycin
clindamycin
lincosamides are ____ containing
sulfur
MOA lincosamides
include whether bacteriostatic or cidal
bacteriostatic protein synthesis inhibitors
binds 50s subunit (same as macrolides - remember MLS)
name 6 aminoglycosides
tobramycin
neomycin
kanamycin
amikacin
streptomycin
gentamicin
MOA aminoglycosides
cidal or static?
bactericidal
binds 30s ribosomal subunit
true or false
aminoglycosides are primarily active against gram (+)
FALSE
gram (-)
how are aminoglycosides administered and why
parenteral or topical - NOT ORAL
bc of basic alkyl amines
concerns with aminoglycosides
because of basic character, can have strong ionic interaction with anions in otic and renal compartments, causing otic and renal toxicitiy
MOA tetracyclines
static or cidal?
static
binds 30s subunit
clinical concerns with tetracyclines
under 8 yrs old - permanent teeth staining
also drug drug interaction with metal ions - *milk, iron, antacids
briefly explain structure of tigecycline
minocycline + 9-glycylamido moeitiy
this 9-glycyl amido gives it enhanced activity
MOA tigecycline
same as tetracycline
bacteriostatic - binds 30s subunit, blocking entry of amino-acyl tRNA into A site of ribosome
color of tigecycline
oragee
differentiate between resistance of tetracycline vs tigecycline
tigecycline has less resistance bc not affected by ribosomal protection or efflux of the drug (while tetracyclines are susceptible to these)
2 tetracycline derivatives and name the difference (structurally)
tigecycline and eravacycline
tigecycline has addition of 9-glycylamido moeity on minocycline
eravacycline has 2 changes. fluorine atom at C7 and pyrrolidinoacetamido on C9 (both on D ring!!)
BOTH have better resistance profile
