BETA-LACTAMASE INHIBITORS Flashcards
Initial combinations of β-lactamase-resistant and β-lactamase-sensitive penicillins had limited success.
Failures were due to poor penetration, reversible binding, and β-lactamase induction
Early Challenges in β-Lactamase Inhibitor Therapy:
Breakthrough Discovery
β-Lactamase Inhibitor
Clavulanic acid
sulbactam and tazobactam.
Thienamycins
a naturally occurring β-lactamase inhibitor) led to renewed interest in combination therapy.
Clavulanic acid
(natural β-lactams) inhibit β-lactamases and bind to PBPs.
Thienamycins
mimic the substrate but cause irreversible enzyme inhibition (“suicide substrates”).
Mechanism-based inhibitors
(e.g., clavulanic acid, sulbactam) → Prolonged inactivation via a heteroatom leaving group.
Class I inhibitors
e.g., carbapenems) → Transient inhibition without a leaving group.
Class II inhibitors
Are used with β-lactam-sensitive penicillins to treat β-lactamase-producing bacteria.
Clavulanic acid, sulbactam, tazobactam
(a Class II inhibitor) has potent antibacterial activity along with β-lactamase inhibition.
Imipenem
Group A β-lactamases (serine enzymes)
Generally inactivated by Class I inhibitors.
Group C β-lactamases (cephalosporinases)
Resistant to Class I inhibitors.
Group B metallo-β-lactamases (Zn²⁺-dependent)
Not inactivated by Class I inhibitors.
an antibiotic isolated from Streptomyces clavuligeris.
Structurally, it is a 1-oxopenam without the 6-acylamino side chain of penicillins.
Contains a 2-hydroxyethylidene moiety at C-2.
Clavulanic acid
Weak antibacterial activity, similar to 6-APA, making it useless as a standalone antibiotic.
Potent inhibitor of S. aureus β-lactamase and plasmid-mediated β-lactamases in Gram-negative bacteria.
Clavulanic acid
a penicillanic acid sulfone (1,1-dioxopenicillanic acid).
A synthetic penicillin derivative that inhibits β-lactamases from S. aureus and many Gram-negative bacilli.
Sulbactam
Weak intrinsic antibacterial activity.
Enhances the activity of ampicillin and carbenicillin against β-lactamase-producing bacteria (S. aureus, Enterobacteriaceae).
Sulbactam
a penicillanic acid sulfone, structurally similar to sulbactam.
More potent β-lactamase inhibitor than sulbactam and has a broader spectrum than clavulanic acid.
Tazobactam
a β-lactam antibiotic first isolated by Merck from Streptomyces cattleya.
Shares structural features with penicillins and cephalosporins:
Fused bicyclic ring system with a β-lactam and a 3-carboxyl group.
Thienamycin
Broad-spectrum activity against aerobic and anaerobic Gram-positive & Gram-negative bacteria.
Highly active against S. aureus, P. aeruginosa, B. fragilis.
Resistant to most β-lactamases, making it effective against penicillin- and cephalosporin-resistant strains.
Thienamycin
a chemically stable derivative of thienamycin, where the primary amino group is modified to prevent nucleophilic activity.
Cilastatin is a DHP-I inhibitor, preventing renal degradation
Imipenem
The combination (Primaxin) ensures chemical & enzymatic stability but still has a short half-life (~1 hour) due to renal secretion.
Imipenem
Broad-spectrum activity, similar to thienamycin.
Binds to PBPs (1b & 2), inhibiting cell wall synthesis.
Highly resistant to most β-lactamases, including those from Gram-negative bacteria like P. aeruginosa, S. marcescens, and Enterobacter spp..
Imipenem
Effective against:
Aerobic Gram-positive bacteria (S. aureus, S. epidermidis, enterococci, viridans streptococci).
Aerobic Gram-negative bacteria (E. coli, Klebsiella, Serratia, Providencia, Haemophilus, Citrobacter, Proteus, Morganella, Acinetobacter, Pseudomonas spp.).
Anaerobic bacteria (B. fragilis, Clostridium, Peptococcus, Peptidostreptococcus, Eubacterium, Fusobacterium).
Imipenem
Some carbapenems (e.g., imipenem, biapenem) can form __________, which may enhance bacterial penetration.
zwitterions
second-generation carbapenem with extensive clinical evaluation.
Approved as Merrem for treating multiply-resistant bacterial infections and serious conditions like:
Bacterial meningitis, septicemia, pneumonia, and peritonitis.
Administered parenterally
Stable against most β-lactamases, including some carbapenemases.
Meropenem
Second-generation carbapenem with properties similar to meropenem.
Broad-spectrum activity against:
Aerobic Gram-negative and Gram-positive bacteria
Anaerobes
parenteral administration
Biapenem:
β-lactam antibiotics derived from Cephalosporium spp. or synthesized semisynthetically.
Discovered in 1945 by Giuseppe Brotzu, who observed their activity against Gram-positive and Gram-negative bacteria.
Cephalosporins
Abraham and Newton (1948) isolated three key components:
Minimal antibacterial activity
Cephalosporin P1
Abraham and Newton (1948) isolated three key components
Penicillin N
More effective against Gram-negative bacteria (e.g., Salmonella spp.) but less effective against Gram-positive bacteria than penicillin G.
Cephalosporin N
Abraham and Newton (1948) isolated three key components:
– Resistant to S. aureus β-lactamase but initially less potent than penicillins
Cephalosporin C
Semisynthetic Cephalosporins
7-ACA
(7-aminocephalosporanic acid)
Goals of semisynthetic cephalosporins include:
Increased acid stability (for oral use).
Better pharmacokinetics (e.g., improved absorption).
Broader antimicrobial spectrum.
Enhanced resistance to β-lactamases and better penetration.
Lower allergenicity.
Improved tolerance for parenteral administration.
(prodrug of cefuroxime).
Cefuroxime axetil
(prodrug of cefpodoxime).
Cefpodoxime proxetil
β-lactamase-resistant that become active after metabolism.
alkoximino-cephalosporins
the only cephalosporin that can be administered both orally and parenterally.
Cephradine
-are broad-spectrum antibiotics with antibacterial effectiveness comparable to ampicillin.
-more resistant to inactivation by β-lactamases, especially from Gram-positive bacteria, than ampicillin
-exhibit uniquely potent activity against most Klebsiella species.
Cephalosporins
-show different levels of resistance to β-lactamases depending on the enzyme’s source and properties.
-generally more resistant than most penicillins to hydrolysis by β-lactamases from S. aureus and Bacillus subtilis. This resistance is due to the cephem ring system, not the acyl group.
Cephalosporins
Some inducible β-lactamases (Group C) which hydrolyze cephalosporins more rapidly than penicillins.
cephalosporinases
resists β-lactam antibiotics primarily through:
β-lactamase production (enzymatic degradation).
Reduced penetration of the antibiotic through the bacterial cell envelope.
P. aeruginosa
Effective Antipseudomonal Cephalosporins
certain cephalosporins demonstrate useful activity against P. aeruginosa, including:
Cefoperazone
Moxalactam
Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
associated with an increased risk of hypoprothrombinemia (vitamin K deficiency-related bleeding)
Cephalosporins
Cephalosporins are categorized into:
first-, second-, third-, and fourth-generation based on:
Time of discovery
Antimicrobial properties
(Keflex, Keforal) was specifically designed as an oral semisynthetic cephalosporin.
-remains stable in acid
-Recommended especially for urinary tract infections (UTIs) and sometimes for upper respiratory tract infections (URTIs).
-Similar antibacterial activity to cephalothin and cephaloridine.
Cephalexin
the only cephalosporin available in both oral and parenteral forms.
-very similar to cephalexin and can be considered a partially hydrogenated derivative.
Cephradine
a semisynthetic derivative of 7-ADCA with a D-hydroxyphenylglycyl group at the 7-acyl position.
-Well absorbed orally, reaching 75–80% of the plasma levels of its structural analog, cephalexin.
-Allows once-daily dosing, a key advantage over cephalexin.
Cefadroxil (Duricef)
a semisynthetic cephalosporin introduced in the U.S. in 1979.
-Synthesized via ozonolysis, followed by halogenation.
Cefaclor (Ceclor)
-(Zinacef) belongs to the second generation, though it features methoximinoacyl substitution, a characteristic of many third-generation cephalosporins.
- The syn-alkoximino group enhances β-lactamase resistance.
-
Cefuroxime
It is a lipophilic, acid-stable oral prodrug that is hydrolyzed to cefuroxime by intestinal and/or plasma enzymes during absorption.
Cefuroxime axetil (Ceftin)
Prodrug of Cefpodoxime
designed for oral administration.
Hydrolyzed by esterases in the intestinal wall and plasma to release the active drug
Cefpodoxime proxetil (Vantin)
Two Categories of Newer Cephalosporins
Orally active β-lactamase–resistant cephalosporins.
Parenteral β-lactamase–resistant antipseudomonal cephalosporins.
Chemically Novel Third-Generation Cephalosporin
a unique analog of oximino cephalosporins.
Resistant to β-lactamase hydrolysis
Orally active with rapid & nearly complete absorption.
Highest oral bioavailability among third-generation cephalosporins.
Ceftibuten (Cedax)
Fourth-Generation Cephalosporin
a parenteral, β-lactamase–resistant cephalosporin
Potency matches first-generation cephalosporins against Gram-positive bacteria.
Potency matches third-generation cephalosporins against Gram-negative bacteria.
Excreted largely unchanged in the urine.
Cefpirome (Cefrom)
Innovative siderophore cephalosporin with broad Gram-negative coverage.
GR-69153:
MRSA-active cephalosporin with better killing speed than vancomycin.
TOC-039
were first isolated from saprophytic soil bacteria in Japan and the United States.
Monobactams
(SQ 26,445) was the first discovered but had weak antibacterial activity despite high β-lactamase resistance.
Sulfazecin
became a successful monobactam antibiotic after optimizing structural modifications.
Aztreonam
Monobactam antibiotic, synthesized completely
Binds exclusively to PBP 3 in Gram-negative bacteria.
Does not induce chromosomal β-lactamase production.
Aztreonam (Azactam)
Newer monobactam that is orally active.
Highly resistant to β-lactamases.
Similar antibacterial spectrum to aztreonam.
Tigemonam
was the first aminoglycoside, discovered in 1944 by Schatz and associates.
Success led to further discoveries, primarily from Streptomyces species
Streptomycin
Major Aminoglycosides (Marketed in the U.S.)
Naturally occurring:
Kanamycin
Neomycin
Paromomycin
Gentamicin
Tobramycin
Netilmicin
Semisynthetic Aminoglycosides
Amikacin (derived from kanamycin A)
a related aminoglycoside, is only used for gonorrhea
Spectinomycin
Named due to their amino sugars linked by glycosidic bonds.
Contain at least one aminohexose and, in some cases, a pentose (e.g., streptomycin, neomycin, paromomycin).
aminoglycosides
most effective against serious systemic infections caused by aerobic Gram-negative bacilli.
Preferred agents: Kanamycin, gentamicin, tobramycin, netilmicin, amikacin
aminoglycosides
Most effective for tuberculosis (TB), brucellosis, tularemia, and Yersinia infections.
Streptomycin
Used mainly for amebic dysentery
Paromomycin
aminoglycosides and β-lactams can have a synergistic effect:
β-lactam weakens the bacterial cell wall, allowing better aminoglycoside penetration.
Primary Target: Bacterial Ribosomes
bind to the 30S ribosomal subunit, inhibiting protein synthesis initiation.
interfere with translation fidelity, leading to misreading mutations and incorporation of incorrect amino acids into proteins
Aminoglycoside
equally effective at blocking initiation and causing misreading
Streptomycin
inhibits initiation of protein synthesis but does not cause misreading.
Spectinomycin
All aminoglycosides are bactericidal except
spectinomycin, which is bacteriostatic
Aminoglycosides Resistance is commonly due to enzymatic inactivation by bacterial enzymes such as:
Aminoacetyltransferases (AAC) → Acetylate amino groups.
Phosphotransferases (APH) → Phosphorylate hydroxyl groups.
Nucleotidyltransferases (ANT) → Adenylate hydroxyl groups.
are naturally resistant due to the lack of respiration-driven transport mechanisms required for aminoglycoside uptake.
Anaerobic bacteria
enable resistance to spread between bacterial species via conjugation (direct contact).
Plasmid-encoded R factors
